The Human Obesity Gene Map
The Human Obesity Gene Map:
The 2003 Update
Eric E. Snyder,* Brandon Walts,* Louis Pérusse,† Yvon C. Chagnon,‡ S. John Weisnagel,† Tuomo Rankinen,*
and Claude Bouchard*
Abstract
SNYDER, ERIC E., BRANDON WALTS, LOUIS
PÉRUSSE, YVON C. CHAGNON, S. JOHN
WEISNAGEL, TUOMO RANKINEN, AND CLAUDE
BOUCHARD. The human obesity gene map: the 2003
update. Obes Res. 2004;12:369 – 439.
This is the tenth update of the human obesity gene map,
incorporating published results up to the end of October
2003 and continuing the previous format. Evidence from
single-gene mutation obesity cases, Mendelian disorders
exhibiting obesity as a clinical feature, quantitative trait loci
(QTLs) from human genome-wide scans and animal crossbreeding experiments, and association and linkage studies
with candidate genes and other markers is reviewed. Transgenic and knockout murine models relevant to obesity are
also incorporated (N ⫽ 55). As of October 2003, 41 Mendelian syndromes relevant to human obesity have been
mapped to a genomic region, and causal genes or strong
candidates have been identified for most of these syndromes. QTLs reported from animal models currently number 183. There are 208 human QTLs for obesity phenotypes
from genome-wide scans and candidate regions in targeted
studies. A total of 35 genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA
sequence variation in specific genes to obesity phenotypes
continue to grow, with 272 studies reporting positive associations with 90 candidate genes. Fifteen such candidate
genes are supported by at least five positive studies. The
obesity gene map shows putative loci on all chromosomes
except Y. Overall, more than 430 genes, markers, and
*Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State
University, Baton Rouge, Louisiana; †Division of Kinesiology, Department of Social and
Preventive Medicine, Faculty of Medicine, Laval University, Sainte-Foy, Québec, Canada;
and ‡Psychiatric Genetic Unit, Laval University Robert-Giffard Research Center, Québec,
Canada.
Address correspondence to Claude Bouchard or Eric E. Snyder, Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808-4124.
E-mail: [email protected]
Copyright © 2004 NAASO
chromosomal regions have been associated or linked with
human obesity phenotypes. The electronic version of the
map with links to useful sites can be found at http://
obesitygene.pbrc.edu.
Key words: human obesity gene map, association, linkages, Mendelian disorders, quantitative trait loci
Introduction
The interest for the compendium of putative human obesity genes continues to be very strong. This paper is the
tenth in a series (1–9) on the status of the human obesity
gene map; this is the ninth report published in Obesity
Research. As in previous versions of the map, the current
publication incorporates material published up to the end of
October 2003. The review includes publications that have
dealt with a variety of phenotypes pertaining to obesity;
such phenotypes include BMI, body-fat mass, percentage of
body fat, abdominal fat, fat-free mass, skinfolds, resting
metabolic rates, plasma leptin levels, and other components
of fat distribution and energy balance. As in previous updates, negative findings are not systematically reviewed but
are briefly introduced when such data were available to us.
The interested reader will notice that a good number of
genes and genomic positions are now supported by multiple
studies and, at times, more than one line of evidence.
The present synthesis includes sections dealing with single-gene and digenic human obesity cases, Mendelian disorders exhibiting a phenotype of relevance to human obesity, quantitative trait loci (QTLs)1 from rodent and other
animal model studies, human linkage studies including genome scans performed to identify QTLs of obesity or obesity-related phenotypes, association studies in humans with
specific genes and polymorphisms, and a comprehensive
1
Nonstandard abbreviations: QTL, quantitative trait locus; Tg, transgenic; KO, knockout;
NCBI, National Center for Biotechnology Information; OGMDB, Obesity Gene Map
Database; AHO, Albright Hereditary Osteodystrophy; WAGR, Wilms’ tumor-aniridiagenital anomalies-mental retardation; md, Mahoganoid; LH, luteinizing hormone; AR,
androgen; DH, double heterozygote; Lod, logarithm of odds; cM, centimorgan(s).
OBESITY RESEARCH Vol. 12 No. 3 March 2004
369
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
pictogram of the 2003 human obesity gene map. A section
deals with transgenic (Tg) and knockout (KO) mice, the
phenotypes of which include alterations in adiposity levels
or a trait relevant to obesity. The references to each entry in
the current human obesity gene map are provided for convenience. We are using gene symbols and chromosomal
locations given in the Locus Link website (http://www.
ncbi.nlm.nih.gov/LocusLink) available from the National
Center for Biotechnology Information (NCBI). The Appendix provides a complete list of genes and map locations
cited in this paper.
The search for the relevant genetic literature is undertaken through a variety of sources: PubMed searches using
a combination of key words, authors, and journals; continuous reviews of obesity and genetics journals; personal
collection of reprints; and papers made available to us by
colleagues from around the world. Each collaborating author is assigned an area of the report for closer scrutiny of
the material available and for preparing the summary of
studies relevant to that area. The electronic version of the
human obesity gene map with numerous useful links is
available at http://obesitygene.pbrc.edu.
Bioinformatics Issues
The data management requirements for this review have
increased significantly since the Obesity Gene Map was
first published in 1996. The online Obesity Gene Map
Database (OGMDB) was created in 2000 to give users
additional querying and browsing capability and to facilitate
the accurate creation of the map figure. This is the first year
in which full capabilities of the database were exploited,
enabling us to create the map and tables in an automated
fashion. The online OGMDB (http://obesitygene.pbrc.edu)
contains HTML (hypertext markup language) versions of
the tables (created on demand), complete with hypertext
links to the corresponding OGMDB data objects.
The OGM database and website were made possible by
three key software components. ACeDB (10,11) (A C.
elegans DataBase) is an object-oriented database environment initially built to support the Caenorhabditis elegans
genome sequencing project (12) but has become a bioinformatics workhorse for a variety of projects including the
SNP Consortium database (13). The database’s web interface was deployed using AceBrowser (14), a collection of
common gateway interface scripts that connect to the
ACeDB server to generate generic database query forms
and display documents. The tables were created using the
application programming interface known as AcePerl (14).
This code library allows a Perl script to retrieve data from
the database and manipulate it programmatically. AcePerl
also greatly reduced the time required to update the cytogenetic and sequence map positions of loci in the database.
The browsing and querying capabilities of OGMDB have
brought to light even more acutely that our ability to draw
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OBESITY RESEARCH Vol. 12 No. 3 March 2004
conclusions from a large-scale analysis of the obesity literature is limited. One major problem is the poor standardization in the description of polymorphisms such as those
reported in Table 1. The use of a standard nomenclature
[such as that proposed by Antonarakis et al. (15)] for the
representation of polymorphisms at the amino acid and
nucleotide level could prevent confusion and loss of information. Furthermore, it would be helpful if all residue
numbering were done with reference to a standard sequence
such as those available in GenBank or European Molecular
Biology Laboratory. In addition, as new mutations and
polymorphisms are identified, they should be deposited in
the Database of Single Nucleotide Polymorphism (dbSNP),
particularly when population frequency information is
available (for submission information see http://www.ncbi.
nlm.nih.gov/SNP).
Another critical issue has to do with the lack of standardized vocabularies for describing obesity phenotypes and the
populations in which they are studied. We currently index
125 distinct study traits, which reduce to ⬃100 after merging trivial variants. The latter subset shares many common
features that could probably be represented by a series of
hierarchical relationships. The same is true of the 83 study
populations and demographic characteristics (age, sex, ethnic origin, etc.) that have been identified in this year’s
inventory. Much work into defining gene function relationships has been done under the auspices of the Gene Ontology Consortium (16). However, there are no widely accepted ontologies for describing human phenotypic data or
populations. A move to create structured vocabularies appropriate for obesity research reporting would facilitate
communication and data mining activities in the future.
Single-Gene and Digenic Obesity Cases
In the past year, no novel single-gene obesity syndromes
have been described. However, there has been more activity
on the melanocortin-4 receptor (MC4R) gene with several
papers on the functional impact of previously and newly
reported mutations (17–24). The number of sequence variants discovered so far is quite large (well over 50). However, there is often insufficient information in the published
reports on pedigrees and trait transmission. The mutations
retained in Table 1 are those that have been shown to be
functional through in vitro studies or would be strongly
suspected to affect receptor structure (deletions, frameshift
and nonsense mutations). A total of 42 different mutations
in 130 individuals fit these criteria, making MC4R mutations the most prevalent genetic cause of obesity identified
to date. These mutations are typically associated with early
onset and rather severe obesity. However, not surprisingly,
the variation in phenotypic expression of obesity related to
the MC4R gene points to variable penetrance and other
genetic factors. One possible mechanism through which
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 1. Monogenic and digenic nonsyndromic human obesity cases
Gene
Location
LEPR
POMC
1p31.3
2p24.1
PCSK1
5q15
LEP
7q32.2
MC4R
18q21.32
Mutation
N
Age (years)
IVS16 ⫹ 1G ⬎ A
R236G
7133delC
7013G ⬎ T
3804C ⬎ A
G483R
IVS5 ⫹ 4A ⬎ C
G398del
R105W
V50M
S58C
I102S
I170V
279–280insGT
C271Y
3⬘UTR ⫹ 28delC
T112M
R165Q
V253I
335–336insA
I125K
A175T
I316S
Deletion
N97D
N62S
I137T
P78L
V95I
I121T
G181D
A244E
750–751delGA
S94R
960delT
Y35X
-65-(-64)delTG
171delC
G98R
S127L
3
6
1
13 to 19
13
3
1
1
7
3
2
4
2
2
1
2
7
9
1
2
1
1
1
2
2
11
6
5
9
1
1
1
1
1
1
1
1
1
11
1
1
1
2
A244G
3
8 to 50
P299H
2
6 to 27
47–48insG
1
20
BMI (SDS)
53 to 72
(2.9)
References
(192)
(26)
(193)
(193)
(194)
2 to 8
6 to 34
6 to 39
13 to 39
16
13 to 45
8 to 36
8 to 40
37 to 46
33 to 56
(2.8 to 5.4)
(2.1 to 4.2)
(4.1)
(3.8 to 4.4)
43
57
8 to 64
40
41
40
8 to 34
26 to 57
40
40
62
27 to 45
(3.2 to 5.3)
24 to 32
(1.8 to 4.1)
28 to 34
(2.7 to 6.3)
42
(195)
(196,197)
(21,24,198)
(21,24,198)
(24,198)
(21,23,198)
(17,24,199)
(17,22,23,199)
(199)
(23,199,200)
(19,23,199)
(19,22,23,199)
(17)
(17,22)
(17,22)
(17,22)
(17)
(17,22)
(17,21,22)
(23,201)
(19,23,24)
(19)
(19)
(19)
(19)
(19)
(19)
(19)
(18,19,202,203)
(204)
(204)
(21,205)
(24,206)
(24,206)
(24,206)
(207)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 1. (continued)
Gene
PPARG
PPP1R3A
Location
3p25.2
7q31.2
Mutation
N
Age (years)
BMI (SDS)
T150I
I170V
L250Q
I301T
1
2
1
2
52
20
60
30 to 35
R165W
5
40 to 75
5
1
1
10
5
11 to 58
50
30 (3.8)
68 (8.5)
54 to 57
(10 to 10.4)
33 to 62
(2.1 to 10)
30 to 57
4 to 81
21 to 49
28 to 41
26 to 31.4
732–733insGATT
Y287X
L106P
631–634delCTCT
553–555delAAAinsT
1984–1985delAG
References
(207)
(23,207)
(207)
(207)
(207)
(208)
(22)
(22)
(17,19,24,202,203,209)
(27)
Status as of October 2003.
N represents the number of published cases.
SDS stands for standard deviation BMI scores and are shown in parentheses.
these mutations affect body weight is loss of normal regulation of food intake (17). Two studies have reported an
association with bulimia (18,25).
As for the other genes, one group described 2 unrelated
children with obesity (2.9 and 3.4 SD scores for BMI), both
carrying a missense R236G mutation in the POMC gene,
not found in a control population (26). This mutation disrupted the dibasic cleavage site between ␤-melanocyte stimulating hormone and ␤-endorphin, causing the formation of
a fusion protein that only weakly activates the receptor. The
mutation co-segregated with early-onset obesity over three
generations in one family.
One report pertained to a family in which all affected
members with overweight or obesity (and insulin resistance) were double heterozygotes for a premature stop
mutation 553–555delAAAinsT (creating a frameshift at
codon 185 and a stop codon at 186) in PPARG and a
frameshift/premature stop mutation 1984 –1985delAG
(creating a frameshift at codon 662 and a stop codon at
668) in PPP1R3A, a gene that encodes protein phosphatase 1, muscle-specific regulatory subunit 3, involved
in carbohydrate metabolism (27). Two affected members
of another family were carriers of the PPP1R3A mutation, suggesting that other genes could be involved as
well. The oligogenic obesity cases identified thus far
could all be ascribed to a single-gene defect. The previous paper appears to be the first to report on cases in
which two hits in different genes were necessary for the
patients to be obese. We have high-lighted this report
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OBESITY RESEARCH Vol. 12 No. 3 March 2004
because we feel that it will be followed by many others
as the oligogenic nature of many obesity cases is progressively revealed.
Mendelian Disorders
Updated references for all Mendelian disorders exhibiting
obesity as one of their clinical features and new additions
are described in Table 2. Among the autosomal dominant
syndromes, several dozen new mutations in the GNAS1
gene have been discovered by different groups in patients
with Albright Hereditary Osteodystrophy (AHO) (28 –32).
These mutations were confirmed to affect function. Exclusive maternal transmission of mutations was reported by
one group, suggesting a role of parental imprinting of the
GNAS1 gene (30). There exists a form of AHO with no
resistance to parathyroid hormone. In this condition called
pseudopseudohypoparathyroidism, the classical features of
AHO such as obesity are present. The STK25 gene, coding
for a kinase involved in heterotrimeric G protein signaling,
is absent as a result of micro-deletions at 2q27 described in
these patients and, thus, is a strong candidate gene for this
condition (33–35). Among the lipodystrophy syndromes,
several patients with either generalized or partial lipodystrophy combined with other clinical features have been
reported (36 –39). All carried mutations in the lamin A
(LMNA) gene.
As for non-Dunnigan familial partial lipodystrophy
(FPLD), another family was reported with a mutation in the
PPARG gene (40). All five affected members carried an
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 2. Obesity-related Mendelian disorders with known map locations
OMIM
no.
Syndrome
Locus
Candidate
gene*
References
Autosomal recessive
203800
209901
209900
600151
600374
603650
209900
607590
269700
606158
212065
216550
601538
227810
139191
Alstrom syndrome
Bardet-Biedl syndrome 1
Bardet-Biedl syndrome 2
Bardet-Biedl syndrome 3
Bardet-Biedl syndrome 4
Bardet-Biedl syndrome 5
Bardet-Biedl syndrome 6
Bardet-Biedl syndrome 7
Berardinelli-Seip congenital lipodystrophy 1
Berardinelli-Seip congenital lipodystrophy 2
Carbohydrate-deficient glycoprotein type 1a
Cohen syndrome
Combined pituitary hormone deficiency
Fanconi-Bickel syndrome
Isolated growth hormone deficiency
2p13.1
11q13.1
16q13
3p13-p12
15q22.33
2q31
20p12.2
4q27
9q34.3
11q13
16p13.2
8q22.2
5q35.3
3q26.31
7p14
ALMS1
BBS1
BBS2
BBS3*
BBS4
BBS5*
MKKS
BBS7
AGPAT2
BSCL2
PMM2
COH1
PROP1
SLC2A2
GHRHR
(210–213)
(50,51,214–217)
(217–219)
(220–222)
(217,223–226)
(227,228)
(229–231)
(49)
(52,232,233)
(52,234–236)
(237)
(53,238,239)
(240,241)
(54,55,242–247)
(248,249)
FGFR3
GNAS1
STK25
AHO2*
ANCR*
ANMA*
LMNA
PPARGC1
INSR
COL8A2
VSX1
IPW
PWCR1
SNRPN
MAGEL2
NDN
MKRN3
SIM1
PRKAR1A
TBX3
THRB
TBX3
WT1
PAX6
(250–253)
(254–267)
(33–35)
(268)
(269)
(270)
(36–39,271–276)
(40,41,277)
(278–285)
(286)
(42,287)
(288–305)
Autosomal dominant
100800
103580
103580
103581
105830
605746
151660
604517
147670
122000
605020
176270
Achondroplasia
Albright hereditary osteodystrophy
Albright hereditary osteodystrophy (PPHP)
Albright hereditary osteodystrophy 2
Angelman syndrome with obesity
Anisomastia
Familial partial lipodystrophy, Dunnigan
Familial partial lipodystrophy, non-Dunnigan
Insulin resistance syndromes
Posterior polymorphous corneal dystrophy (Chr 1)
Posterior polymorphous corneal dystrophy (Chr 20)
Prader-Willi syndrome
603128
188830
181450
190160
181450
194072
Prader-Willi-like syndrome (chr 6q)
Primary pigmented nodular adrenocortical disease
Schinzel syndrome
Thyroid hormone resistance syndrome
Ulnar-mammary syndrome
WAGR syndrome
4p16.3
20q13.32
2q37.3
15q11-q13
15q11-q12
16q13-q21
1q23.1
4p15.31
19p13.3
1p34.3
20p11.21
15q11.2
15q11.2
15q12
15q11.2
15q11.2
15q11.2
6q16.3
17q24.3
12q24.21
3p24.1
12q24.21
11p13
11p13
(291,301,302,305–309)
(48)
(310)
(311)
(43,310,312)
(44,45,313–315)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 2. (continued)
OMIM
no.
Syndrome
Locus
Candidate
gene*
References
X-linked
301900
303110
Borjeson-Forssman-Lehmann syndrome
Choroideremia with deafness
309550
300148
300218
300238
176270
312870
Fragile X syndrome with Prader-Willi-like phenotype
MEHMO syndrome
Mental retardation X-linked, syndromic 7
Mental retardation, X-linked, syndromic 11
Prader-Willi-like syndrome, X-linked
Simpson-Golabi-Behmel 1
300209
309585
Simpson-Golabi-Behmel 2
Wilson-Turner syndrome
Xq26.3
Xq21.1
Xq21.2
Xq28
Xp22.13-p21.1
Xp11.3-q22.1
X26-q27
Xq23-q25
Xq26.2
X
Xp22
Xq21.2-q22
PHF6
DFN3
CHM
FMR1
MEHMO*
MRXS7*
MRXS11
GPC3
GPC4
SGBS2*
WTS*
(56,316–318)
(319,320)
(60–63)
(321–323)
(324)
(57,325)
(308,326)
(327–333)
(334)
(335,336)
Status as of October 2003.
OMIM, Online Mendelian Inheritance of Man.
* Symbols with asterisks are the National Center for Biotechnology Information LocusLink symbols for the traits rather than for the genes
and are used when no candidate genes are known.
F388L mutation that affected transcriptional activity and
receptor activity. Another group described severe insulin
resistance with partial lipodystrophy in carriers of a P467L
mutation in PPARG (41).
In cases of posterior polymorphous corneal dystrophy, a
corneal endothelial dystrophy in which obesity has been
observed, two loci seem to be involved. Mutations in the
COL8A2 gene at 1p34.2-p32.3 and the VSX1 gene (at
20q11), which encodes a homeodomain transcription factor
(42), have been reported. The Prader-Willi-like syndrome
linked to 6q16.2-q14 and the SIM1 gene are now reported
here with the Mendelian syndromes. New mutations have
been reported for ulnar-mammary (Schinzel) syndrome
(43). For the Wilms’ tumor-aniridia-genital anomalies-mental retardation (WAGR) syndrome, a further case of obesity
with hyperphagia has been described (44). One recent report
described several mutations in the PAX6 gene in patients
with aniridia, a condition of iris hypoplasia. One patient had
WAGR syndrome, in which PAX6 was deleted, making
PAX6 a possible candidate gene (45).
One of the classical forms of central obesity is Cushing’s
syndrome, in which obesity, insulin resistance, glucose abnormalities, hypertension, and other features are invariably
found, all of which are caused by pathologically elevated
levels of cortisol. The causal gene for the only known
inherited form of this disease has recently been reported by
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OBESITY RESEARCH Vol. 12 No. 3 March 2004
2 groups (46,47). Primary pigmented nodular adrenocortical
disease with Cushing’s syndrome is caused by mutations in
the regulatory subunit R1A of the protein kinase A gene
(PRKAR1A), encoding a key mediator of cyclic adenosine
3⬘,5⬘-monophosphate signaling in mammals. This disease is
part of the multiple neoplasia syndrome, the Carney complex (48).
In the autosomal recessive syndrome category, another
Bardet-Biedl syndrome (BBS) locus has been found, BBS7.
The gene causing the corresponding syndrome codes for a
protein of unknown function (49). Two groups reported on
the complex inheritance in BBS (50,51).
An exploration of the heterogeneity of congenital generalized lipodystrophy (Berardinelli-Seip Congenital Lipodystrophy) led to the identification of 12 different mutations
in AGPAT2 in 27 pedigrees and 9 mutations in BSCL2 in
11 other pedigrees (52). Two other studies described patients with the syndrome who did not carry any mutations in
these genes, suggesting a possible additional BSCL locus.
The causal gene, COH1, in Cohen syndrome, in which
obesity is a minor component, was recently identified by a
Finnish group (53). Affected individuals carried mutations
encoding a transmembrane protein with a presumed role in
vesicle-mediated sorting and intracellular protein transport.
Finally, several new mutations have been described in the
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 3. Natural single-gene mutation in mouse models of obesity
Mouse
Mutations*
Human homolog
Chr Genes Inheritance
Diabetes (db)†
4
Fatty liver dystrophy (fld) 12
Fat (fat)
8
OLETF
5
Little
11
Obese (ob)
6
Tubby (tub)
7
Mahogany (mg)
2
Mahoganoid (md)
16
y
2
Agouti yellow (A )
Lepr
Lpin1
Cpe
Cckar
Gh
Lep
Tub
Atrn
Mgm1
Ay
Recessive
Recessive
Recessive
Recessive
Recessive
Recessive
Recessive
Recessive
Recessive
Dominant
Chr
Genes
Gene product
References
1p31
2p21
4q32
4p15.2-p15.1
8q12.3
7q31.3
11p15.5
20p13
16p13.3
20q1.2-q12
LEPR
LPIN1
CPE
CCKAR
GH
LEP
TUB
ATRN
MGRN1
ASIP
Leptin receptor
Lipin
Carboxypeptidase E
Cholecystokinin receptor A
Growth hormone
Leptin
Insulin signaling protein
Attractin
Mahogunin, ring finger 1
Agouti signaling protein
(337,338)
(339)
(340)
(341,342)
(343)
(344)
(345–347)
(348,349)
(64)
(350)
Status as of October 2003.
Chr, chromosome.
* The strain carrying the Adult (ad) dominant mutation on chromosome 7 is now extinct.
† Homologous to rat fat (fa)/corpulent (cp).
GLUT2 or SLC2A2 gene that causes the Fanconi-Bickel
syndrome (54,55).
As for the X-linked syndromes, a novel D333del mutation in the candidate gene for Borjeson-Forssman-Lehmann
syndrome has been reported (56). A second family with
Shashi X-linked mental retardation syndrome with prominent obesity has been described (57). In Simpson-GolabiBehmel 1 syndrome patients with overgrowth, two studies
expanded on the phenotypic and genotypic spectrum of the
disease (58,59). Finally, we have added to this year’s list a
fragile X syndrome with Prader-Willi-like phenotype. Fragile-X syndrome is a common cause of mental retardation.
However, a subtype with Prader-Willi-like phenotype has
been described in which mutations in the FMR-1 gene are
present, with no deletions at the PWS locus at 15q11-q12
(60 – 63). Patients with this syndrome often present with
severe obesity.
Single-Gene Mutations in Mice
Table 3 summarizes the mouse models of obesity caused
by a defect in a single gene. There is only one addition this
year. The Mahoganoid (MGRN1) gene has been cloned
from the mouse coat color mutant Mahoganoid (md) (64).
MGRN1 encodes a 494-amino acid protein containing a
C3HC4 RING domain. The human homologue is 81% identical at the amino acid level. Three mutations have been
observed (md, md2J, and md5J). They are all due to large (5to 8-kb) retroviral insertions (exon 2, intron 2, intron 11,
respectively), resulting in a 10- to 20-fold lower expression
level of the normal transcript. Mahoganoid diminishes the
obesity of AY mice (65), but does not suppress obesity
caused by a high-fat diet (64).
Knockout and Transgenic Models
New KO and Tg mice have evidenced that other genes
have the potential to impact obesity-related phenotypes. We
have retained only those models in which the gene has a
human equivalent (Table 4). Five new KO or Tg gene
models and one transgenic model for a chromosomal duplication/deletion have been added to the compendium. Two
hormonal genes (luteinizing hormone or LH and androgen
receptor or AR) have been related to obesity-related phenotypes. Tg female mice overexpressing a chimeric bovine LH
␤-subunit/human chorionic gonadotropin ␤-subunit COOHterminal extension (bLHb-CTP) became obese with a 32%
increase in body weight at 5 months of age (66). Food intake
was increased and thermogenic activity reduced (66). Using
a conditional targeting technique based on the Cre-loxP
system, AR knockout male mice showed late-onset obesity
at 30 weeks of age (67). Food intake remained normal
whereas white adipose tissue accumulated, which suggests
that ARs act as a negative regulator of adipocyte development (67).
Secreted protein acidic and rich in cysteine/osteonectin/
BM-40 (SPARC) is a matrix-associated protein that elicits
changes in cell shape. SPARC-null mice have a greater
deposit of subcutaneous fat arising from an increase in size
and number of adipocytes (68). The immune-modulating
cytokine interleukin-6 is expressed both in adipose tissue
and hypothalamic nuclei that regulate body composition.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
375
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 4. Knockout and transgenic rodent models relevant to obesity
Rodent
Chr
Human
Gene
Mutations
5
7
X
2
2
12
X
17
5
7
7
Acc2
ApoC1
Ar
Atrn
Ay
Batf(A-ZIP/F)
Brs3
C3
Cckar
Cebp
Cebp
Knockout
Transgenic
Knockout
Naturally occurring
Naturally occurring
Transgenic
Knockout
Knockout
Naturally occurring
Knockout
Knockout
13
8
9
11
Chrm3
Cpe
Cyp19
Df(11)(17)*
Smcr
Dgat
Gene
Product
References
12q24.1
19q13.2
Xq11.2-q12
20p13
20q11.2-q12
14q24.3
Xq26-q28
19p13.3
4p15.2-p15.1
20q12-q13.1
20q13.13
ACACB
APOC1
AR
ATRN
ASIP
BATF
BRS3
C3
CCKAR
CEBPA
CEBPB
(351)
(352)
(67)
(348,349)
(350)
(353)
(354)
(355)
(341,342)
(356)
(357)
Knockout
Naturally occurring
Knockout
Transgenic
1q41-q44
4q32
15q21
17p11.2
CHRM3
CPE
CYP19A1
del(17)(p11.2)* SMCR
Acetyl CoA carboxylase 2
Apolipoprotein C1
Androgen receptor
Mahogany
Agouti yellow
Regulator of transcription factor B-ZIP
Bombesin receptor 3
Acylation-stimulating protein
OLETF
CCAAT enhancer binding protein
CCAAT/enhancer binding protein
(C/EBP), beta
Muscarinic receptor M3
Fat
Transferase Aromatase
Smith-Magenis syndrome
Knockout
8q-ter
DGAT1
(360)
Transgenic
17p11.2
13
8
Dp(11)(17)*
Smcr
Drd1a
Eif4ebp1
Knockout
Knockout
5q34-q35
8p12
dup(17)(p11.2)(p11.2)*
SMCR
DRD1
EIF4EBP1
Acyl CoA: diacylglycerol acyl
transferase
Smith-Magenis syndrome
(361)
(362)
3
17
3
15
Fabp4 (aP2)
Fshr
GabtI
Gdc1
Knockout
Knockout
Transgenic
Transgenic
8q21
2p21
3p25-p24
12q13.2
FABP4
FSHR
SLC6A1
GPD1
2
6
15
6
11
5
10
1
Ghrh
Ghrhr
Gpr24
H1r
Hcrt
Hdh
Hmga2
Hsd11b1
Transgenic
Naturally occurring
Knockout
Knockout
Knockout
Transgenic
Knockout
Transgenic
20q11.2
7p14
22q13.3
3p25
17q21
4p16.3
12q15
1q32-q41
GHRH
GHRHR
GPR24
HRH1
HCRT
HD
HMGA2
HSD11B1
9
2
5
6
4
7
12
2
Icam1
Il1rn(Il-1ra)
Il-6
Lep
Lepr
Lhb
Lpin1
Mapk8ip
Knockout
Knockout
Knockout
Naturally occurring
Naturally occurring
Transgenic
Naturally occurring
Knockout
19p13.2
2q14.2
7p15.3
7q32.2
1p31.3
19q13.32
2p21
11p11.2
ICAM1
IL1RN
IL6
LEP
LEPR
LHB
LPIN1
MAPK8IP1
8
3
3
7
Mt
Nhlh2
Pkar2b
Plin
Knockout
Knockout
Knockout
Knockout
16q13
1p12-p11
1q12
15q26
MT1A
NHLH2
PRKAB2
PLIN
Dopamine receptor D1
Eukaryotic translation initiation factor
4E binding protein 1
Fatty acid binding protein 4
Follicular stimulating hormone receptor
Gamma-aminobutyric acid transporter I
alpha-glycerol phosphate
dehydrogenase
Growth hormone releasing hormone
Little
G protein-coupled receptor 24
Histamine receptor H1
Hypocretin (Orexin)
Huntingtin
Component enhancesome Hmgic
Hydroxysteroid (11-beta)
dehydrogenase 1
Intercellular adhesion molecule 1
interleukin 1 receptor antagonist
Interleukin 6
Obese
Diabetes
Luteinizing hormone beta polypeptide
Fatty liver dystrophy
Mitogen-activated protein kinase 8
interacting protein 1
Metallothionein I and II
Neural transcription factor 2
Protein kinase A RIIb
Perilipin
15
11
376
Chr
OBESITY RESEARCH Vol. 12 No. 3 March 2004
(358)
(340)
(359)
(72)
(72)
(363)
(364)
(365)
(366)
(367)
(343)
(368)
(369)
(370)
(371)
(372)
(373)
(374)
(375)
(69)
(344)
(337,338)
(66)
(339)
(71)
(376)
(377)
(378)
(379,380)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 4. (continued)
Rodent
Chr
Gene
Human
Mutations
Chr
Gene
10
11
2
2
Pmch
Ppy
Prkcq
Ptpn1
Transgenic
Transgenic
Transgenic
Knockout
12q23.3
17q21
10p15.1
20q13.1-q13.2
PMCH
PPY
PRKCQ
PTPN1
5
12
11
Ptprb
Sdc1
Sparc
Knockout
Transgenic
Knockout
12q15-q21
2p24.1
5q33.1
PTPRB
SDC1
SPARC
8
Srebf1/Srebf2
Transgenic
17p11.2
SREBF1
11
Stat5
Knockout
17q11.2
STAT5A
7
7
5
Tgfb1
Tub
Vgf
Transgenic
Naturally occurring
Knockout
19q13.31
11p15.5
7q22
TGFB1
TUB
VGF
Product
Melanin concentrating hormone
Pancreatic polypeptide
Protein kinase C, theta
Protein tyrosine phosphatase, nonreceptor type 1
Protein tyrosine phosphatase 1 B
Syndecan 1
Secreted protein, acidic, cysteine-rich
(osteonectin)
Sterol regulatory element binding
protein
Signal transducer and activator of
transcription 5
Transforming growth factor, beta 1
Tubby
Neural expressed protein
References
(381,382)
(383)
(70)
(384)
(384)
(385)
(68)
(386,387)
(388)
(389)
(345–347)
(390)
Status as of October 2003.
Chr, chromosome.
*Dp(11)(17) and Df(11)(17) represent an engineered chromosomal duplication or deletion, respectively, of the Smith-Magenis syndrome
region on mouse chromosome 11. Similarly, del(17)(p11.2) and dup(17)(p11.2)(p11.2) refer to the deletion and duplication, respectively,
of the corresponding human chromosomal regions.
Interleukin-6 KO mice showed disturbed carbohydrate and
lipid metabolism resulting in mature-onset obesity (69). In a
Tg model overexpressing a mutated form of protein kinase
C theta (PKC-theta), a dominant negative mutation that
acted specifically in skeletal muscle to invalidate kinase
activity, mice were obese and insulin resistant at 4 months
of age (70), whereas the inactivation of the c-Jun aminoterminal kinase 1 (JNK1) decreased adiposity and improved
insulin sensitivity (71).
Finally, Tg mice carrying a deletion on chromosome 11
[Df(11)17] homologous to the human Smith-Magenis syndrome region at 17p11.2 exhibited marked obesity. In contrast, Tg mice carrying the reciprocal duplication of the
same chromosomal region [Dp(11)17] were underweight
(72). carrying the reciprocal duplication of the same chromosomal region [Dp(11)17] were underweight (72). Examination of the Df(11)17/Dp(11)17 animals suggests that the
phenotype results from a gene dosage effect (72).
QTLs from Crossbreeding Experiments
A total of 183 animal QTLs are now included in our
inventory (Table 5) with equivalent human syntenic regions
determined from the Mouse Genome Database of the Jackson Laboratory (73) and the NCBI Mouse/Human homology maps (74). Only mice crosses have been added to this
year’s review. In previous years, maps described by Yamada et
al. (75) and Jacob et al. (76) were used for the rat, and maps
from the Animal Genome Database in Japan (77) and from the
U.S. Livestock Genome Mapping Projects (78) for the pig.
A cross between fat-preferring C57BL/6J and carbohydrate-preferring CAST/EiJ mice was studied for macronutrient intake (79). Three QTLs for intake of fat (Mnif1 to 3),
three for carbohydrate (Mnic1 to 3), and two for total caloric
intake (Kcal1 and 2) were uncovered (79). A total of 16.4%,
12.8%, and 9% of the variance was explained by these
QTLs for the three phenotypes, respectively. Similarly, A/J
and C57BL/6J strains differ markedly in a number of behavioral traits with A/J mice showing a significantly inhibited exploratory behavior. In an intercross between A/J and
C57BL/6J, a QTL for body weight at 8 weeks (Bw8q1) was
detected and a second one (Bw8q2) in the backcross
(C57BL/6J ⫻ A/J) ⫻ A/J, accounting for 2% and 4% of the
phenotypic variance in body weight, respectively (80). In a
new cross between the heavier and fatter inbred strain
C57BL/6ByJ and strain 129P3/J, two QTLs for body weight
(Bwq5 and Bwq6) and two for adiposity (Adip5 and Adip9)
were observed. They explained 9.1% of each of the variance
in weight and adiposity (81). Double heterozygotes for
insulin receptor and insulin receptor substrate-1 (DH) mice
exhibited a reduction in size and body weight, but showed
OBESITY RESEARCH Vol. 12 No. 3 March 2004
377
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 5. QTLs for obesity phenotypes from animal crosses with putative syntenic locations in the human genome
Cross
Mus musculus
(A/J ⫻ M. spretus) ⫻ C57BL/6J
Mus musculus
129/Sv ⫻ Le/Suz
Mus musculus
129S6 ⫻ C57BL/6J
Mus musculus
A/J ⫻ (C57BL/6J ⫻ A/J)
Mus musculus
AKR/J ⫻ C57L/J
Mus musculus
AKR/J ⫻ SWR/J
QTL
Bw1*
Bw2*
Bw3
Obq2
Obq1
D12Mit38
Lod ⫽ 3.4
Lod ⫽ 6.6
Lod ⫽ 4.3
Lod ⫽ 5.5
Lod ⫽ 8
Lod ⫽ 3.7
Bw8q2
Obq4
Obq3
Dob1
Dob2
Dob3†
Mus musculus C3H/HeJXDBA/2J ⫻ D3Mit127
(BALB/cJ ⫻ C57BL/6J)
Mus musculus
Adip5
C57BL/6J ⫻ 129P3/J
Bwq5
Bwq6
Adip9
Mus musculus
Bw8q1
C57BL/6J ⫻ A/J
Mus musculus
Mob7
CAST/Ei ⫻ C57BL/6J
Mob8
Qlep
Mob6
Bl
Bw
Mus musculus
Pfat1
CAST/Ei ⫻ M16i
Pfat3
Pfat4
Pfat5
Pfat2
Mus musculus
Mnif1
CAST/EiJ ⫻ C57BL/6J
Mnif2
Mnif3
Mnic1
Mnic2
Mnic3
Kcal1
Kcal2
Mus musculus
Carfhg1
CAST/EiJ ⫻ C57BL/6J-hg/hg
Carfhg2
Mus musculus
DBA/2J ⫻ C57BL/6J
378
Statistics
Bw6a
Bw6e
Pfatp6
Bw6c
Pfatp13
Bw6g
Variance
(%)
24
Chromosome
Phenotypes
Animal
Human
References
6.3
12.3
33
Body weight
Body weight
Body weight
Adiposity
Adiposity
Leptin, increased
X
X
X
7
7
7
Xp11-q26
Xq11-q13
Xp22-q27
6q12-q14
19q13.2-q13.3
11q13
(82)
Lod ⫽ 3.3
4
Body weight, 8 weeks
4
6p22.2-p22.3
(80)
Lod ⫽ 4.6
Lod ⫽ 5.1
Lod ⫽ 4.8
Lod ⫽ 3.9
6.1
7
7
4
Adiposity
Adiposity
Adiposity
Adiposity
17
Leptin, 4 months
6q27
11p11.2
1p33-p32
3p21
8q24.1
4q23-q25
(393)
p ⫽ 0.001
17
2
4
9
15
3
Lod ⫽ 4.0
Lod ⫽ 4.4
Lod ⫽ 4.0
Lod ⫽ 3.3
Lod ⫽ 4.4
4.7
4.8
4.3
4.4
2
Adiposity
Body weight
Body weight
Adiposity
Body weight, 8 weeks
9
2
9
16
1
11q23.1-q24.3
20q11.2-q12
3p21.33-q21
21q22.11-q22.2
1q21
(81)
(396)
2q11-q14
5q23-q31
8q22-q23
8q24
20q13.11-q13.13
8p22-p21.3
5q22-q23
Xq26-q26.3
6p21
3p26-p24
Xq13.1
5q31
6p21.3-p21.1
4p15.1
11q25
(397)
7.1
5.4
3.6
6
3.1
3.7
6.8
4.4
6.2
12.5
2
9
4
2
15
15
2
13
15
15
2
8
18
X
17
6
X
17
18
5
9
3p21.3
6p12.1
9p22
11p11.2
Lod ⫽ 8.0
Lod ⫽ 6.0
Lod ⫽ 4.0
Lod ⫽ 6.7
Lod ⫽ 3.4
Lod ⫽ 4.1
Lod ⫽ 7.7
Lod ⫽ 4.9
Lod ⫽ 2.5
Lod ⫽ 5.8
Subcutaneous fat
Body fat, percentage
Leptin level (no obesity)
Subcutaneous fat
Body length
Body weight
Adiposity
Adiposity
Adiposity
Adiposity
Adiposity
Fat, intake
Fat, intake
Fat, intake
Carbohydrate intake
Carbohydrate intake
Carbohydrate intake
Kilocalorie intake
Kilocalorie intake
Fat content
Fat content
Lod ⫽ 3.3
Lod ⫽ 4
Lod ⫽ 4.9
Lod ⫽ 3.2
Lod ⫽ 5.3
Lod ⫽ 4.4
3
4
20
4
20
5
6-week weight
6-week weight
Predicted fat, percent
6-week weight
Predicted fat, percent
6-week weight
1
6
6
5
13
9
1q31-q33
2p12
3p14.1-p12
4q12-q13
5q22-q31
6q12-q16
Lod ⫽ 5.7
Lod ⫽ 4.7
Lod ⫽ 5.2
Lod ⫽ 7.3
Lod ⫽ 4.3
Lod ⫽ 2.5
OBESITY RESEARCH Vol. 12 No. 3 March 2004
(391)
(392)
(394,395)
(83)
(80)
(79)
(398)
(399,400)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 5. (continued)
Cross
Mus musculus
Du6 ⫻ DuK
Mus musculus
Du6i ⫻ DBA/2
Mus musculus
F⫻L
Mus musculus
JU/CBA ⫻ CFLP (P6)
Mus musculus
KK-A(y) ⫻ C57BL/6J
Mus musculus
KK/H1Lt ⫻ C57BL/6J
Mus musculus
MH ⫻ C57BL/6J
QTL
Statistics
Chromosome
Variance
(%)
Phenotypes
Animal
Human
References
Bw6k
Bw6j
Pfatp15
Bw6b
Pfatp4
Bw6d
Bw6i
Bw6h
Bw6f
Afw3
Afw1
Afp2
Qbw1
Afw2
Qbw2
Bw4
Afp1
Bw5
Bw16
Bw13
Bw15
Afpq10
Lepq1
Bw14
Afpq6
Afpq9
Afw10
Afw9
Fob1
Lod ⫽ 4.9
Lod ⫽ 3
Lod ⫽ 8.6
Lod ⫽ 3.3
Lod ⫽ 5
Lod ⫽ 4.3
Lod ⫽ 4.1
Lod ⫽ 5.7
Lod ⫽ 6.9
F ⫽ 4.7
F ⫽ 4.89
F ⫽ 4.89
Lod ⫽ 2.7
F ⫽ 4.79
Lod ⫽ 7.6
F ⫽ 4.79
F ⫽ 4.89
F ⫽ 10.4
F ⫽ 7.52
F ⫽ 11.7
F ⫽ 7.36
F ⫽ 7.48
F ⫽ 7.58
F ⫽ 25.9
F ⫽ 8.92
F ⫽ 18.5
F ⫽ 8.56
F ⫽ 24.9
Lod ⬎ 3.3
7
3
20
4
20
5
4
6
9
7.7
10–13
8.3
6.9
8.3
17
23.1
10–13
5.4
3.9
6
3.8
3.9
4.4
12.3
4.6
9.1
4.5
12
4.9
6-week weight
6-week weight
Predicted fat, percent
6-week weight
Predicted fat, percent
6-week weight
6-week weight
6-week weight
6-week weight
Abdominal fat
Abdominal fat
Abdominal fat, percentage
Abdominal fat
Abdominal fat
Body mass
Body weight
Abdominal fat
Body weight
Body weight
Body weight
Body weight
Abdominal fat, percentage
Leptin
Body weight
Abdominal fat, percentage
Abdominal fat, percentage
Abdominal fat, percentage
Abdominal fat, percentage
14-weeks fat, percent
17
14
15
4
4
5
13
11
7
13
4
3
3
11
11
11
4
1
11
5
13
12
14
7
17
7
12
7
2
2q34
2p13.3
7p22
7p14-p13
7p15
8p21-p12
15q11-12
19p13.3-p13.2
19q13.3
(403)
2q21-q37
(404)
Fob2
Lod ⫽ 3.3
19.5
12
7p22-q22
Fob3
Fob4
Bw19
QbwX
Bwq2
Bwq1
Obq5
KK7
Obq6
Hlq1
Batq1
Hlq2
Hlq3
Batq2
Hlq4
Hlq5
Fatq1
Lod ⫽ 11.3
Lod ⫽ 3.3
Lod ⫽ 24.4
Lod ⫽ 24.4
Lod ⫽ 4.1
Lod ⫽ 3.1
Lod ⫽ 6.3
Lod ⫽ 4.4
Lod ⫽ 5
Lod ⫽ 5.6
Lod ⫽ 4
Lod ⫽ 3.7
Lod ⫽ 3.8
Lod ⫽ 3.5
Lod ⫽ 4.7
Lod ⫽ 4.06
Lod ⫽ 8
14.4
7.3
17–20
17–20
26
15
17
11.7
14-weeks fat, percent
(female)
14-weeks fat, percent
14-weeks fat, percent
10-week weight
10-week weight
Adiposity
Body weight
Adiposity (females)
Inguinal fat
Adiposity (males)
Heat loss
Brown fat
Heat loss
Heat loss
Brown fat
Heat loss
Heat loss
Gonadal fat
15
X
X
X
6
4
9
7
X
1
1
2
3
3
3
7
1
8q24.2-q24.3
Xq12-q21.2
Xq28
4.7
3.3
3.1
3.1
2.8
3.9
3.4
5.9
6p21
8p23.1-p22
8q24-qter
9p24-p23
9p24
12q24
15q23-q25
17p13
19q13.3
1q43
1p34-p33
3q25
4q23-q27
7p13-p11.2
17q12-q22
17q21-q22
3p26-p25
6q16
11q23-q24
11q21
Xq26-q28
1q21-q41
1q41-q42.1
2p13-q13
3q25
4q28-q31
8q21.3-q22.1
16p12-p11.2
18q21.3
(401,402)
(404)
(405)
(406)
(407)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
379
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 5. (continued)
Cross
Mus musculus
Mus spretus ⫻ C57BL/6J
Mus musculus
NSY ⫻ C3H/He
Mus musculus
NZB/B1NJ ⫻ SM/J
Mus musculus
NZO ⫻ SJL
Mus musculus
NZO ⫻ SM
Mus musculus
NZO/H1Lt ⫻ NON/Lt
Mus musculus
Quackenbush-Swiss ⫻ C57BL/6J
Mus musculus
SM/J ⫻ A/J
Mus musculus
SM/J ⫻ LG/J
Mus musculus
TSOD ⫻ BALB/cA
380
QTL
Statistics
Chromosome
Variance
(%)
Mob4
Mob2
Mob3
Mob1
Nidd3nsy
Lod ⫽ 3.4
Lod ⫽ 4.8
Lod ⫽ 4.8
Lod ⫽ 4.2
Lod ⫽ 6.8
5.9
7.1
7
6.5
Mob5‡
Lod ⫽ 3.6
Nob1
Lod ⫽ 3.8
Obq8
Lod ⫽ 6.4
Obq9
Lod ⫽ 6.7
Obq7
Lod ⫽ 6
Obq14
Obq12
Obq4
Lod ⫽ 9.2
Lod ⫽ 4.5
Lod ⫽ 6.3
Obq11
Obq13
Obq10
Lod ⫽ 4.1
Lod ⫽ 9.3
Lod ⫽ 6.4
Obq15
Lod ⫽ 6.6
Nzoq1
Phenotypes
Animal
Human
References
Mesenteric fat
Femoral fat
Body fat, percentage
Body fat, percentage
Epididymal fat
15
6
12
7
6
5p14-p13
7q31.2-q31.3
14q32.1-q32
16p12.1-p11.2
2p14-p12
(409)
36
Body fat
2
20q13.1-q13.3
(410)
16.8
BMI
5
4p15
(411)
1
1q31
(412)
1
1q22-q23
1
2q33.1
6
17
3p26
4p15
6q27
5
6
2
7q22-q36
7p14
11p13
7
11p15.5
Lod ⫽ 3.8–9.4
16
Retroperitoneal fat,
percentage
Percent mesenteric fat
(females
Mesenteric fat, percentage
(males)
Mesenteric fat, percentage
Gonadal fat, percentage
Inguinal fat, percentage
(males)
Gonadal fat, percentage
Mesenteric fat, percentage
Gonadal fat, percentage
(males)
Gonadal fat, percentage
(males)
Body weight
1
6p12-p11
(413)
Nzoq2
Qsbw
Lod ⫽ 4
p ⫽ 0.009
40
BMI
Body weight
12
10
14q31-q32
12q22-q23
(414)
Bwq4
Bwq3
Qlw13
Qlw12
Qlw1
Qlw3
Qlw5
Qlw18
Qlw9
Qlw4§
Qlw7§
Qlw10§
Qlw14
Qlw2
Qlw11
Adip2
Lod ⫽ 4.8
Lod ⫽ 4.6
Lod ⫽ 1.9
Lod ⫽ 2.3
Lod ⫽ 2.3
Lod ⫽ 2.3
Lod ⫽ 2.8§
Lod ⫽ 2.8§
Lod ⫽ 1.8
Lod ⫽ 2.4
Lod ⫽ 2
Lod ⫽ 4.9
Lod ⫽ 2.1
Lod ⫽ 2.9
Lod ⫽ 2.6
Lod ⫽ 3.5–6.2
18
8
13
12
1
3
6
18
9
4
7
10
14
2
11
6
5q32-q35
16q22-q23
1q43
2p24-p23
2q35-q36
3q25-q26
3p26-p24
5q31
6p12.1
9q31-q32
11p15
12q21
14q11.2
15q11.2-q22.2
22q12
Adip3
Nidd6
Nidd5
Lod ⫽ 9.7
Lod ⫽ 4.65
Lod ⫽ 5.91
Body weight at 10 weeks
Body weight at 10 weeks
Adiposity
Late weight gain
Late weight gain
Late weight gain
Late weight gain
Adiposity
Adiposity
Late weight gain
Late weight gain
Weight
Weight
Late weight gain
Late weight gain
Adiposity/weight
(females)
Adiposity (males)/weight
Body weight
Body weight
OBESITY RESEARCH Vol. 12 No. 3 March 2004
6
6
2.4
1.9
8.4
3.4
2.4
2
2.6
2.4
9.2
10.9
7
1
2
1q25
2q22-q23
(408)
(415)
(409,416–418)
(419)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 5. (continued)
Cross
Mus musculus
Wild Mus musculus castaneus ⫻
C57BL/6J
Rattus norvegicus
(OLETF ⫻ BN) ⫻ OLETF
Rattus norvegicus
Dahl ⫻ MNS
Rattus norvegicus
GK ⫻ BN
Rattus norvegicus
GK ⫻ F344
Rattus norvegicus
Lepr(fa)/Lepr(fa) 13M ⫻ WKY
Rattus norvegicus
OLETF ⫻ BN
Rattus norvegicus
OLETF ⫻ F344
Rattus norvegicus
SHR ⫻ BB/OK
Rattus norvegicus
SHR ⫻ Wild
Rattus norvegicus
WOKW ⫻ DA/K
Sus scrofa
Berkshire ⫻ Yorkshire
Sus scrofa
European wild boar ⫻ Large
White
QTL
Statistics
C10bw1
C10bw4
Lod ⫽ 10.7
Lod ⫽ 3.7
C10bw5
C10bw7
Lod ⫽ 3.4
p ⫽ 0.00001
C10bw2
Lod ⫽ 3.3
C10bw3
C10bw6
Lod ⫽ 3.7
Lod ⫽ 4.3
Dmo9
Dmo1
Dmo4
Dmo7p
Dmo6p
Dmo5
Dmo10
DAHL3
Lod ⫽ 3.5
Lod ⫽ 8.2–14
Lod ⫽ 4.4–5.5
Lod ⫽ 4.9–5.4
Lod ⫽ 3.5–3.6
Lod ⫽ 3.5–3.6
Lod ⫽ 3.5–3.6
p ⫽ 0.00003
Nidd/gk6
Nidd/gk1
bw/gk1
Nidd/gk5
Niddm1
Lod ⫽ 3.2
Chromosome
Variance
(%)
Phenotypes
Animal
Human
2
13
2q24.2
5q13
13
12
5q14.3
14q23-q24.2
9
15q21-q22
11
X
17q24-q25
Xp22.2-p21.2
13
1.4-g body weight
0.9-g body weight
(females)
0.8-g body weight (males)
Body weight (males;
epistatic)
1.1-g body weight
(females)
1.3-g body weight (males)
1.4-g body weight
(females)
Adiposity index
Body weight
Adiposity index
Adiposity index
Adiposity index
Adiposity index
Body weight
Body weight
11
1
1
7
6
3
11
3
3q26.1-q28
10q23-q24
11p15.5-p15.4
12q22-q23
14q32
19p13.2-q13.3
21q22.1
10q25
23.5
Body weight
Adiposity
Body weight
Body weight
Body weight
17
1
7
8
1
1q41-q44
3p21
8q21-q24
11q22-q23
10q24-q26
12q22-q23
17pter-q23
7q22
16q13
References
(420)
(421)
(422)
(423)
(424)
Weight1
Niddm3
Qfa12
Qfa1
Lod ⫽ 3
Lod ⫽ 2.2
8.3
6.9
BMI, female
BMI, female
7
10
12
1
Dmo1
Lod ⫽ 6
11.6
Body weight
1
10q23-q24
(426)
Obs5
Obs1
Obs3
Obs4
Obs2
Obs6
Imfq1
SHR4
SHR1
SHR10
Lod ⫽ 5.4
Lod ⫽ 5.1
Lod ⫽ 5.9
Lod ⫽ 5.3
Lod ⫽ 4.2
Lod ⫽ 4.5
Lod ⫽ 3.4
Lod ⫽ 3.1
Lod ⫽ 3.3
Lod ⫽ 3.5
12.4
13.8
13.4
16.5
11.3
13.8
5
14
32
Retroperitoneal fat
Mesenteric fat
Mesenteric fat
Retroperitoneal fat
Retroperitoneal fat
Retroperitoneal fat
Intramuscular fat
Body weight (females)
Body weight (males)
Body weight (males)
14
2
8
9
4
14
1
4
1
10
4q12-q13
5p13-p12
6q12-q13
6p21
7q11.2-q36
7p13-p12
9q12
7p15.3
11p15.5
17pter-q23
(427,428)
WOKW1/
Q5 ms1
WOKW1/
Q1 ms1
SSC7
SSC1
SSC4
SSC5
FAT1
Lod ⫽ 4.5
16
BMI
5
1p36-p31
Lod ⫽ 4.9
31
30-week body weight
1
3p21
F ⫽ 13.8
F ⫽ 11.3
F ⫽ 11.8
F ⫽ 9.5
p ⫽ 0.0001
6.9
4.8
6
4.8
9.7
Back fat
Back fat
Weight
Back fat
Body fat, percentage
7
1
4
5
4
6p21.3
9q32-q34.1
(432)
1q21-q25
(433–435)
(425)
(429)
(430)
(404,431)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 5. (continued)
Cross
Sus scrofa
Iberian ⫻ Landrace
Sus scrofa
Meishan ⫻ (Dutch Landrace
⫻ Large White)
Sus scrofa
Meishan ⫻ Duroc, Hampshire,
Landrace
Sus scrofa
Meishan ⫻ Dutch
Sus scrofa
Meishan ⫻ Gottingen
Sus scrofa
Meishan ⫻ Large White
Sus scrofa
Meishan ⫻ White
Sus scrofa
Meishan ⫻ White composite
Sus scrofa
Minghu ⫻ Hampshire, Landrace
Sus scrofa
Wild Boar ⫻ Large White
Bos bovis
Hereford ⫻ CGC
QTL
Statistics
Variance
(%)
Chromosome
Phenotypes
Animal
Human
References
FAT1
F ⫽ 11.1
Back fat depth
4
1q21-q25
(436)
SSC7
SSC2
F ⫽ 18§
F ⫽ 2.7
Back fat thickness
Back fat thickness
7
2
6p21.3
11p15
(437,438)
PigQTL2
F ⫽ 7.9
Average backfat
7
6p21
(439,440)
SSC6q
SSC7
SSC2
SSC6p
SSCX
SSC7
F ⫽ 14.7
F ⫽ 49.4
F ⫽ 24.1
F ⫽ 14.5
F ⫽ 12.8
F ⫽ 19.5
Intramuscular fat
Back fat thickness
Back fat thickness
Intramuscular fat
Intramuscular fat
Back fat thickness
6q
7
2
6p
X
7
1p33-p32
6p21.3
11p15
16q22-qter
Xq11.2-q22
6p21.3
(441,442)
Mid-back fat depth
4
1q21-q25
(444)
Back fat depth
Weight
Back fat depth
Back fat thickness
Back fat thickness
Back fat thickness
Back fat thickness
Back fat thickness
Back fat thickness
Back fat thickness
42-day weight
7
1
X
4
8
5
6
7
1
X
13
6p21.3
9q32-q34.1
Xq11.2-q22
(445,446)
6p21.3
9q32-q34.1
Xq11.2-q22
3p11
(447)
¶
Back fat depth
2p
11p15.5
(448,449)
⫺24 kg live weight
17
4
(450)
0.1–0.2
18
BFM4
SSC7
SSC1
SSCX
SSC4
SSC8
SSC5
SSC6
SSC7
SSC1
SSCX
PIT1
F ⫽ 10.4–20.5
F ⫽ 39.4–94.9
F ⫽ 37.4–71.8
F ⫽ 14.9–15.3
F ⫽ 9.5
F ⫽ 13.4–15.1
F ⫽ 11.9
F ⫽ 14.7
F ⫽ 15.4
F ⫽ 32.3
F ⫽ 3.34
3–4
1–2
2–5
1–2
IGF2q
F ⫽ 7.1
10.4
BTA17LW F ⫽ 8
(443)
Status as of October 2003.
Adip, adiposity; Afp, abdominal fat percent; Afpq, abdominal fat QTL; Afw, abdominal fat weight; Batq, brown adipose tissue QTL; BFM4, backfat QTL
on chromosome 4; Bl, body length; BTA17LW, bovine chromosome 17 live weight; Bw, body weight; bw/gk, body weight/Goto-Kakizaki; Bw6, body weight
at 6 weeks; Bw8q, QTL for body weight at 8 weeks of age; Bwq, body weight QTL; C10bw, castaneus 10-week body weight QTL; Carfhg1 (Q5Ucd1-fp):
carcass fat in high growth mice 1; DAHL3, Dahl rat body weight QTL on chromosome 3; Dmo, diabetic mouse; Dob, dietary obese; FAT 1, pig QTL with
major effect on fitness; Fatq, fat QTL; Fob, fat obesity; Hlq, heat loss QTL; IGF2q, QTL located near the gene for insulin-like growth factor 2; Imfq1,
intramuscular fat QTL 1; Kcal, cumulative kilocalorie intake; KK7, KK mouse chromosome 7 region; Lepq, leptin receptor QTL; m, maternal effect; Minc,
macronutrient intake, carbohydrate; Mnif, macronutrient intake, fat; Mob, multigenic obesity; na, Not available; Nidd, non-insulin dependent diabetes
mellitus; Nidd3n (Nidd3nsy), non-insulin-dependent diabetes mellitus 3 in NSY; Niddm, non-insulin dependent diabetes mellitus; Nob1, New Zealand obese
QTL 1; Nzoq, New Zealand obese contributed QTL; Obq, obesity QTL; Obs, Obesity QTL; p, paternal effect; Pfat, polygenic fatness; Pfatp, predicted fat
percent; PigQTL2, Pig backfat thickness QTL; PIT1, POU-domain transcriptional regulator; Q1 ms1, metabolic syndrome QTL on chromosome 1; Q5 ms1,
metabolic syndrome QTL on chromosome 5; Qbw, QTL body weight; Qfa, QTL LEPRfa; Nidd/gk, non-insulin dependent diabetes/Goto-Kakizaki; Qlep, QTL
for leptin; Qlw, QTL late weight gain (6 to 10 weeks); Qsbw, Quackenbush-Swiss body weight; SHR, salt hypertensive rat; SSC, swine chromosome;
WEIGHT1, body weight QTL 1; WOKW, Wistar Ottawa Karlsburg Rt1uW.
* Also observed in the cross (C3H/He ⫻ A/J) ⫻ M. spretus (391).
† Also observed in the CAST/Ei ⫻ C57B1/6J F2 intercross (451).
‡ Also observed in the cross CAST/Ei ⫻ C57BL/6J (396).
§ Replicated.
¶Yu T, Wang L, Tuttle C, Rothschild M. Mapping genes for fatness and growth on pig chromosome 13: a search in the region close to the pig PIT1 gene.
J Anim Breed Genet. 1999;116:269 – 80.
Synteny relationships established according to the following references: (74,75,77,78,452).
382
OBESITY RESEARCH Vol. 12 No. 3 March 2004
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
a marked hyperinsulinemia and diabetes on a C57BL/6J
background, and only a mild elevation of insulin and with
no diabetes on a 129S6 background. The cross DH-C57BL/6J
⫻ DH-129S6 uncovered a QTL for hyperleptinemia on
chromosome 7 in the vicinity of the uncoupling protein 2/3
gene cluster (82). Finally, a QTL for leptin has been found
on chromosome 3 in the UM-HET3 mice obtained from the
cross [BALB/cJ ⫻ C57BL/6J] ⫻ [C3H/HeJXDBA/2J].
These mice showed an average difference of 0.9 ng/mL
from mean leptin levels (5.3 and 5.0 ng/mL for females and
males, respectively) (83).
Association Studies
The evidence for associations between candidate genes
and obesity-related phenotypes is summarized in Table 6. A
total of 272 studies covering 90 candidate genes have reported significant associations. Of these, 58 studies (43
candidate genes) were published during the past year. This
year’s update includes 23 new candidate gene entries. These
new reports indicate that body weight, BMI, overweight,
and obesity were associated with DNA sequence variation
in ACE (84), ADRB2 (85), ADRB3 (86), AGRP (87),
APM1 (88,89), APOA1 (90), APOA4 (91), ATP1A2 (92),
CAPN10 (93), ESR1 (94), FABP2 (95), FOXC2 (96),
GNB3 (97), HSD11B1 (98), IL6 (99), IL6R (100), IRS2
(101), LIPC (102), LIPE (103), MACS2 (104), MC4R (19),
NCOA3 (105), NR0B2 (106), NR3C1 (107,108), PGR
(105), PPARA (109), PPARG (110 –114), SCARB1 (112),
SLC6A3 (115), TCF1 (116), and TGFB1 (117).
Body fatness-related phenotypes (fat mass, percentage of
body fat, sum of skinfolds) showed associations with markers in AGRP (87), AR (118), ATP1A2 (92), CNTFR (119),
ESR1 (94), FOXC2 (96), IRS2 (101), LIPE (103), PPARA
(109), and PPARG (113). Phenotypes reflecting body fat
distribution (abdominal visceral fat, waist circumference,
waist-to-hip girth ratio, sagittal diameter) were associated
with ADRB2 (120,121), APM1 (89), APOA1 (90), AR
(122), CYP19A1 (123), DF (124), ESR1 (94), HSD11B1
(98), IL6 (99), IRS2 (101), LIPC (102), MACS2 (104),
PPARG (113,114), TGFB1 (117), and UCP1 (125). Resting
energy expenditure, thermic effect of feeding, and 24-hour
lipid oxidation phenotypes were associated with ADRB3
(126), IL6 (127), LEPR (128), PPARG (129), and
PPARGC1 (130) markers, whereas adipocyte size and lipolysis showed associations with polymorphisms in LEPR
(128), PLIN (131), and PPARGC1 (130). Three candidate
genes (ENPP1, MC3R, POMC) were reported to be associated with plasma leptin levels (132–134).
Seven studies reported associations between candidate
genes and changes in body weight and body composition
(132). The UCP1 (135) and NR3C1 (136) loci showed
associations with spontaneous changes in body weight and
adiposity over time, whereas weight gain during pregnancy
was associated with the GNB3 polymorphism (137). Mark-
ers in the GNB3 (138) and PNMT (139) loci were reported
to be predictive of sibutramine-induced weight loss. Response to a lifestyle based weight-loss program was associated with a marker in the ADRB3 locus (140) and endurance training-induced changes in body composition showed
associations with the ADRB2 polymorphisms (141)
In addition to the positive studies summarized above, we
identified 40 studies dealing with 27 candidate genes in
which there were no associations between DNA sequence
variations and obesity-related phenotypes. Among these
studies, the most frequent were those pertaining to markers
of UCP2 (142–145) (four studies), ADRA2B (146 –148),
ADRB2 (149 –151), PPARG (86,152,153), and RETN
(154 –156) (three studies each). Other markers yielding negative findings were those related to ACE (157), ADRB3
(158), APOE (159,160), CAPN10 (161), CYP27B1 (162),
DGAT1 (163), DRD2 (164), EDN1 (165,166), ESR1 (167),
F7 (168), FABP2 (169), GNB3 (170), GPR10 (171), IL6
(172,173), IRS1 (174), IRS2 (174), LEPR (175), LPL (176),
NOS3 (177), NR0B2 (178), SORBS1 (179), and TNF (180).
Linkage Studies
A total of nine linkage studies with obesity-related phenotypes were reported over the last 12 months, including five
new genome-wide scans (53,181–184). The other four studies
were attempts to replicate previous linkages reported on chromosomes 3q27 (185), 7q22-q35 (186), 2p and 10p (103), and
10p and 20q (187). Results from these studies are described
below, and the new QTLs have been added to Table 7.
A genome scan of BMI allowing for potential effects of
imprinting was performed on a sample of 1909 individuals
from 255 three-generation pedigrees who took part in the
Rochester Family Heart Study (182). Linkage between BMI
and 372 autosomal markers was tested in the whole sample
(893 sibpairs) and in two age groups: children 5 to 11 years
old (101 sibpairs) and young adults 17 to 30 years old (173
sibpairs). Analyses of all sibpairs revealed significant evidence of linkage on 1p36 with marker D1S552 [logarithm
of odds (Lod) ⫽ 2.03; p ⫽ 0.002)]. In children 5 to 11 years,
evidence of linkage to BMI was found on chromosomes
5q34-q35 (Lod ⫽ 2.48 with marker D5S1471), 16p13
(Lod ⫽ 3.12 with D16S404), 16p11.2-p13.1 (Lod ⫽ 2.45
with D16S764), 20p12-p13 (Lod ⫽ 3.55 with D20S482),
and 20p11.2-pter (Lod ⫽ 4.08 with D20S851). None of
these regions showed evidence of parent-specific linkage
(imprinting). However, evidence of linkage of BMI to paternally derived alleles was found on chromosomes 3p23p24 (Lod ⫽ 1.77 with D3S3038), 10p14-q11.2 (Lod ⫽ 1.89
with D10S1423), and 12p12-pter (Lod ⫽ 1.83 with
GATA49D12), whereas linkage to maternally derived alleles was found on chromosome 4q31.1-q33 (Lod ⫽ 1.89
with D4S1629). In the 17- to 30-years of age group, evidence of linkage was found on 8p11-q13 (Lod ⫽ 2.05 with
D8S1113) and 14q11.2-q21.3 (Lod ⫽ 1.95 with D14S742),
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
whereas linkage to paternally derived alleles was found on
chromosomes 4q31-qter (Lod ⫽ 1.84 with D4S2417) and
8p (Lod ⫽ 1.98 with D8S277).
Another genome scan based on data from 89 German
families with two or more obese children and adolescents
was published in 2003 (188). Obese sibships included one
sibling with a BMI ⱖ95th percentile and other siblings with
BMI ⱖ90th percentile. Linkage with obesity was tested
with 452 genetic markers with an average intermarker distance of 8.4 centimorgans (cM). Only three regions provided evidence of linkage with Lod scores ⱖ1.5; these
regions were on chromosomes 10p11.23 (Lod ⫽ 2.24 with
D10S197), 11q11-q13.1 (Lod ⫽ 1.65 with D11S1313), and
19q12 (Lod ⫽ 1.97 with D19S414).
Three other genome-wide linkage analyses of obesity
based on BMI have been reported. One was undertaken in
769 subjects from 182 Nigerian families with an average
BMI of 21.3 kg/m2 (181). Subjects were genotyped for 402
autosomal markers, an average map density of 9 cM. The
highest Lod scores were observed on chromosomes 7p14
with marker D7S817 (Lod ⫽ 3.83) and 11q22 with marker
D11S2000 (Lod ⫽ 3.35). Significant evidence of linkage
was also observed on chromosomes 1q21 (Lod ⫽ 2.24 with
marker D1S534) and 8p22 (Lod ⫽ 2.34 with marker
GATA151F02). In another genome scan, linkage between
BMI and 384 markers was tested in 157 subjects from seven
large nuclear families from the Old Order Amish population, selected on evidence for the segregation of a single
locus with major effects on BMI (184). Sibpair linkage
analyses identified QTLs for BMI on chromosomes 1p32
(p ⬍ 0.009), 5q35 (p ⬍ 0.004), 7q35 (p ⬍ 0.004 for 3
markers), 8q23 (p ⬍ 0.005), and 11q22 (p ⬍ 0.008). Typing
of additional markers on 7q35 confirmed the linkage with
BMI in a 10- to 15-cM region downstream from the leptin
gene (184). Finally, another genome scan of obesity was
undertaken in a cohort of families ascertained for probands
with obstructive sleep apnea (183). Given that obesity is a
major risk for patients suffering from obstructive sleep
apnea, the authors tested linkage between BMI and 373
autosomal markers, with a mean spacing of 9.1 cM, genotyped in 349 subjects from 66 white pedigrees. Results
revealed that BMI was linked to markers located on chromosomes 2p22 (Lod ⫽ 3.08), 7p22 (Lod ⫽ 2.53), and
12q21 (Lod ⫽ 3.41).
Finally, four other studies were undertaken to test for
linkages between BMI and markers located at specific chromosomal regions in an effort to replicate previous findings.
In a study based on a sample of 1422 twin pairs from the
Swedish Twin Registry (103), no evidence of linkage to five
markers located in the area of the QTL reported earlier on
2p21 (189) or to 8 markers located in the area of the QTL
reported on 10p12-p11 (190) was observed. In an attempt to
replicate a linkage for BMI on 3q27 (191), a sample of 545
individuals from 128 African-American families were geno384
OBESITY RESEARCH Vol. 12 No. 3 March 2004
typed for 15 markers evenly spaced in a 112-cM region
around the peak linkage previously identified. Evidence of
linkage was found between marker D3S2427 at 188.3 cM
and BMI (Lod ⫽ 2.4) (185). When analyses were repeated
in a larger sample comprising 1163 individuals from 330
families, the peak linkage (Lod ⫽ 4.3) was found at 187.6
cM between markers D3S3676 and D3S2427. The authors
concluded that 3q27 should be considered as a strong candidate region in the search for obesity-related genes (185).
To identify genes potentially involved in obesity on chromosome 7q, Li et al. (186) examined linkage between BMI
and 21 markers located in a 40-cM region flanking the
leptin gene on 7q22.1-q35. Significant evidence of linkage
was obtained with D7S692 (Lod ⫽ 2.75) and D7S523
(Lod ⫽ 2.11) on 7q31.1. These markers define a 20-cM
region upstream of the leptin gene which could harbor an
obesity-related gene (186). The last linkage study at a candidate region was undertaken on 200 white families with
542 siblings and 44 African-American families with 125
siblings, with the aim of testing epistatic interactions among
five loci located on chromosomes 10 and 20 (187). Linkage
analyses performed in the combined sample of 244 families
revealed evidence of linkage on 10p11.2-cent with obesity
(BMI ⱖ27 kg/m2), on 10q22 with waist circumference and
BMI, on 10q25 with obesity and WHR, and on 20q13.1q13.2 with percentage of body fat (187).
Discussion
Figure 1 depicts the human obesity gene map and incorporates ⬎430 loci from single-gene mutation rodent models
of obesity, human obesity cases due to single-gene (or
digenic) mutations, and QTLs from crossbreeding experiments and genome-wide scans, all relevant Mendelian disorders that have been mapped, genes or markers that have
been shown to be associated or linked with an obesity
phenotype, and genes that have been evidenced in Tg or KO
experiments. The map reveals that putative loci affecting
obesity-related phenotypes are found on all but chromosome Y of the human chromosomes. In the case of chromosome 21, it is important to note that there are only two
loci from animal models and none that has been confirmed
in human studies. It is obvious that several genomic regions
are characterized by a high density of concordant positive
findings. As we now have a final draft of the human genome
sequence and, with it, a more exhaustive annotation of the
genome, we expect continuous advances in the understanding of the genetic basis of the predisposition to human
obesity.
The number of genes and other markers associated or
linked with human obesity phenotypes continues to expand.
The progress made over the last decade is exemplified in the
numbers collated in Table 8. The human obesity gene map
has become significantly more detailed and complex since
the first version developed in 1994. Of interest is the fact
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Figure 1: The 2003 human obesity gene map. The map includes all obesity-related genes and QTLs identified from the various lines of
evidence reviewed in this article. This year’s map consists of an updated 850-band-resolution cytogenetic map overlaid with build 34 of the
human genome sequence available from NCBI (http://www.ncbi.nlm.nih.gov). This allows the human genes (as abbreviated in the Tables
and Appendix and located to the right of each chromosome in this figure) to be placed at precise positions on both the sequence and the
cytogenetic map. For all loci, we used the name preferred by UniSTS or LocusLink. Regions of the human genome homologous to the
animal QTLs from Table 5 are represented on the human map (on left). The ruler to the left of each figure represents kilo basepairs.
Chromosomes are drawn to scale only within a given page. These maps, along with information from this report, can be browsed and
searched interactively at the Obesity Gene Map website (http://obesitygene.pbrc.edu).
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 6. Evidence for association between markers of candidate genes with obesity-related phenotypes
Gene
Location
ABCC8
ACE
ACP1
11p15.1
17q24.1
2p25
ADA
ADRA2A
20q13.12
10q25.3
ADRA2B
2q11.2
ADRB1
ADRB2
10q26.11
5q31-q32
Cases
(N)
232
959
75
265
273
213
72
166
126
931
239
180
494
247
247
247
230
236
508
140
826
366
836
63
277
1576
284
224
ADRB3
8p12-p11.2
24
286
574
185
313
476
553
179
295
83
211
53
350
398
154
586
56
128
1675
254
Phenotype
p
References
Obesity, morbid
Overweight
BMI (in children)
BMI (in NIDDM subjects)
BMI (in NIDDM subjects)
Skinfolds, trunk to extremity ratio (in blacks)
Skinfolds, trunk to extremity ratio (in women)
Basal metabolic rate (in obese nondiabetics)
Body weight, change, 5-year (in nondiabetics)
Body weight, BMI, fat mass
Waist-to-hip ratio
BMI
Body weight, increase (in men)
Change in BMI (in women)
Change in fat mass (in women)
Change in percent body fat (in women)
Change in sum of 8 skinfolds (in men)
Lipolysis
BMI (in Japanese)
BMI, fat mass, fat cell volume
Obesity, BMI, waist-to-hip ratio, waist circumference,
hip circumference
BMI (in women)
Body weight, BMI, waist-to-hip ratio, waist
circumference, hip circumference (in French men)
BMI, fat mass
BMI (in Japanese men)
BMI
Leptin
BMI, abdominal total fat, abdominal subcutaneous fat
(in men)
Leptin, body weight, increase, skinfolds, sum of 8
Body weight, increase
BMI (in Japanese)
Body weight, increase over 20 years, weight, current
Obesity (in those 20 to 35 years old)
BMI (in men)
Obesity (in Japanese children)
BMI
BMI
BMI (in CAD patients)
Obesity, moderate
Obesity
BMI
BMI, abdominal subcutaneous fat, abdominal visceral
fat
Obesity (in sedentary individuals)
BMI, hip circumference (in women)
BMI, fat mass, waist circumference
Body weight, increase over 25 years
Obesity, BMI, percent body fat
Obesity, early onset
0.02
0.014
0.02
0.002
0.0004
0.04
0.002
0.01
0.04
0.05
0.05
0.003
0.01
0.04
0.0008
0.0003
0.03
0.02
0.001
0.001
0.05
(453)
(84)
(454)
(455)
(456)
(457)
(458)
(459)
(460)
(461)
(462)
(463)
(464)
(141)
(141)
(141)
(141)
(465)
(466)
(467)
(468)
0.01
0.002
(469)
(470)
0.05
0.004
0.02
0.03
0.01
(471)
(472)
(85)
(473)
(474)
0.03
0.04
0.009
0.007
0.05
0.05
0.02
0.006
0.05
0.05
0.02
0.05
0.009
0.02
(475)
(476)
(477)
(478)
(462)
(479)
(480)
(481)
(482)
(483)
(484)
(485)
(486)
(487)
0.05
0.03
0.05
0.01
0.05
0.002
(488)
(489)
(490)
(491)
(492)
(493)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 6. (continued)
Gene
Location
Cases
(N)
76
131
261
979
AGRP
16q22.1
AGT
1q42.2
APM1
3q28
APOA1
11q23.3
APOA2
APOA4
1q23.1
11q23.3
APOB
2p24.2
APOD
APOE
3q26.2-qter
19q13.32
AR
Xq12
ATP1A2
1q23.1
CAPN10
2q37.3
CART
5q13.2
CBFA2T1
8q21.3
CCKAR
CNTFR
CYP19A1
CYP7A1
DF
DRD2
4p15.2-p15.1
9p13.2
15q21
8q12.1
19p13.3
11q23.2
394
802
49
335
47
183
253
212
212
135
316
94
413
371
95
95
245
482
482
624
369
375
613
56
232
181
114
164
113
106
122
156
12
12
148
286
612
528
281
1296
465
125
1102
24
392
176
Phenotype
Fat mass (in Thai males)
Fat mass, abdominal visceral fat
BMI
Waist-to-hip ratio, overweight (in men ⬎53 years
old)
BMI
BMI
Waist-to-hip ratio (in women)
Body weight (in obese children)
BMI, percent body fat, fat mass (in whites)
BMI
Fat mass
Percent body fat
Body weight, change
Waist-to-hip ratio
Fat mass (in women ⬎42 years old)
Body weight, waist circumference (in Japanese, in
whites)
BMI
BMI (in obese women)
Sagittal diameter (in obese women)
BMI
BMI (in type 2 diabetics)
Waist-to-height ratio (in type 2 diabetics)
Waist circumference
BMI
BMI, waist-to-hip ratio (in young men)
BMI, percent body fat
Abdominal fat, percent body fat
BMI
BMI
BMI
Waist circumference (in women with a family history
of diabetes)
Waist circumference (in women)
Percent body fat
Percent body fat, respiratory quotient
Respiratory quotient (in young adults)
Fat mass
Body weight
ADRB3 activity in adipocytes (in overweight
individuals)
BMI
Waist-to-hip ratio (in men)
Obesity, BMI
BMI, percent body fat, waist circumference, hip
circumference
Leptin, percent body fat
Fat-free mass
Sagittal diameter (in women)
BMI
Abdominal fat (in MZ twins)
Body weight
Obesity
OBESITY RESEARCH Vol. 12 No. 3 March 2004
p
References
0.05
0.01
0.05
0.05
(494)
(495)
(496)
(497)
0.02
0.03
0.02
0.05
0.003
0.015
0.028
0.013
0.006
0.007
0.008
0.03
(498)
(499)
(500)
(501)
(502)
(87)
(87)
(87)
(503)
(504)
(505)
(506)
0.02
0.014
0.032
0.05
0.048
0.023
0.03
0.003
0.004
0.004
0.04
0.005
0.05
0.006
0.05
(507)
(508)
(508)
(88)
(90)
(90)
(509)
(91)
(510)
(511)
(512)
(513)
(514)
(515)
(516)
0.002
0.01
0.05
0.0001
0.01
0.05
0.004
(122)
(118)
(517)
(518)
(508)
(508)
(519)
0.003
0.002
0.008
0.0002
(93)
(520)
(521)
(522)
0.003
0.011
0.049
0.05
0.05
0.002
0.002
(523)
(119)
(123)
(524)
(124)
(525)
(526)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 6. (continued)
Gene
Location
ENPP1
ESR1
6q23.1
6q25.1
FABP2
4q27
FABP4
FOXC2
8q21
16q24.1
GCGR
17pter
GCK
GHRL
7p13
3p25.3
GNB3
12p13.31
Cases
(N)
320
383
990
293
108
551
551
551
216
507
395
714
644
215
950
58
65
192
737
294
230
20
111
213
181
130
250
114
197
1950
GYS1
HSD11B1
19q13.33
1q32-41
HSD3B1
HSPA1B
HTR1B
HTR2A
1p11.2
6p21.31
6q14.1
13q14.11
HTR2C
Xq24
IGF1
12q23.3
IGF2
11p15.5
IL6
7p15.3
130
263
263
263
132
517
98
276
264
117
148
589
502
1474
427
271
Phenotype
p
References
Energy expenditure, 24-hour, sleeping metabolic rate
Skinfolds, iliac, skinfolds, triceps
Obesity
Leptin
BMI (in postmenopausal women)
BMI (in middle-aged women)
Percent body fat (in middle-aged women)
Waist circumference (in middle-aged women)
Obesity, android type
BMI, percent body fat
Abdominal fat
BMI
BMI
Percent body fat
Waist-to-hip ratio, waist girth, sagittal abdominal
diameter
Body weight at birth (in males)
BMI (in tall obese children)
Obesity (in women)
Obesity (in men)
Weight gain during pregnancy
BMI (in primiparous women)
Lipolysis
Weight loss with sibutramine
BMI, waist circumference, hip circumference,
skinfolds (in Nunavut Inuit)
Body weight at birth
BMI
Fat mass, change, body fat, percent change
Lipolysis (subcutaneous, adrenoreceptor-mediated)
BMI (in hypertensives)
Body weight, BMI (in males, white, Chinese and
African)
Obesity
BMI (in children)
Waist circumference (in children)
Waist-to-hip ratio (in children)
Skinfolds, sum of six, 12-year change in
Obesity
BMI (in women with bulimia nervosa)
dietary energy, carbohydrate and alcohol intake (in
obese subjects)
BMI, abdominal sagittal diameter, waist-to-hip ratio
Body weight, gain, antipsychotic-induced
Body weight, loss (in teenage women)
BMI
Percent body fat, fat-free mass, fat mass, fat-free
mass, change in
BMI
Fat mass
BMI (in men)
0.03
0.002
0.03
0.01
0.04
0.05
0.05
0.05
0.0002
0.01
0.008
0.042
0.03
0.02
0.001
(527)
(528)
(529)
(132)
(530)
(94)
(94)
(94)
(531)
(532)
(533)
(95)
(96)
(96)
(534)
0.002
0.001
0.05
0.01
0.006
0.01
0.01
0.0013
0.05
(535)
(536)
(537)
(97)
(137)
(538)
(539)
(138)
(540)
0.02
0.001
0.006
0.004
0.02
0.001
(541)
(542)
(543)
(544)
(545)
(546)
0.03
0.005
0.05
0.05
0.04
0.0002
0.001
0.028
(547)
(98)
(98)
(98)
(548)
(549)
(550)
(551)
0.015
0.0003
0.0001
0.009
0.05
(552)
(553)
(554)
(555)
(556)
0.02
0.05
0.007
(557)
(558)
(99)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 6. (continued)
Gene
Location
IL6R
INS
1q22
11p15.5
INSR
IRS1
19p13.3
2q36.3
IRS2
13q33.3
LDLR
19p13.2
LEP
7q32.2
LEPR
1p31.3
LIPC
15q21.3
LIPE
19q13.31
Cases
(N)
271
124
124
184
758
2734
238
1152
52
75
156
1748
233
233
233
83
131
270
84
112
103
395
unknown
233
211
117
168
84
502
308
335
179
336
220
267
130
268
184
20
62
118
230
234
231
257
117
405
405
396
Phenotype
Waist circumference (in men)
Fasting energy expenditure
Energy expenditure during hyperinsulinemic clamp
Obesity (in women)
Body weight
Body weight
Obesity
BMI
Waist-to-hip ratio (in obese women)
Obesity (in hypertensives)
Leptin (in obese subjects)
BMI (in African Americans)
BMI
Percent body fat
Waist circumference
BMI (in normotensives)
BMI, skinfolds, subscapular, skinfolds, triceps, arm
fat index
Obesity
BMI (in hypertensives)
BMI (in hypertensives)
Body weight, BMI
Leptin
Leptin secretion
Leptin (in obese women)
Obesity (in women)
Leptin
Body weight, decrease
Body weight
BMI, fat mass
Fat-free mass
Body weight, BMI, fat mass (in women)
BMI, fat mass, body weight, loss (in overweight
women)
Overweight/obesity
Leptin, BMI, fat mass (in postmenopausal women)
BMI, abdominal sagittal diameter
Obesity, extreme (in children)
24-hour energy expenditure
Subcutaneous abdominal adipocyte size
Percent body fat
Abdominal total fat, abdominal subcutaneous fat
BMI
BMI
Waist circumference
Abdominal visceral fat
BMI, percent body fat, fat mass, skinfolds, sum of 8
(in white women, in black women)
Waist-to-hip ratio, lipolysis
Obesity (in women)
Percent body fat (in women)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
p
References
0.01
0.012
0.007
0.05
0.009
0.001
0.05
0.0002
0.005
0.05
0.03
0.04
0.02
0.01
0.004
0.008
0.001
(99)
(127)
(127)
(100)
(559)
(560)
(561)
(562)
(563)
(564)
(565)
(566)
(101)
(101)
(101)
(567)
(568)
0.02
0.004
0.04
0.005
0.02
0.05
0.02
0.05
0.04
0.006
0.05
0.005
0.03
0.01
0.006
(569)
(570)
(571)
(572)
(573)
(574)
(575)
(576)
(577)
(578)
(579)
(580)
(581)
(582)
(583)
0.009
0.0001
0.04
0.02
0.02
0.02
0.003
0.03
0.01
0.002
0.002
0.03
0.005
(584)
(585)
(586)
(587)
(128)
(128)
(588)
(589)
(590)
(102)
(102)
(102)
(591)
0.02
0.05
0.05
(592)
(593)
(593)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 6. (continued)
Gene
LMNA
Location
1q23.1
Cases
(N)
380
110
48
306
47
186
LPL
8p21.3
MACS2
16p12.3
MC3R
20q13.2
236
1976
1976
314
MC4R
18q21.32
244
156
NCOA3
NPY
20q13.13
7p15.3
NPY5R
NR0B2
4q32.2
1p35.3
NR3C1
5q31
PGR
PLIN
PNMT
POMC
11q22.2
15q26
17q21.2
2p24.1
PON2
7q21.3
PPARA
22q13.31
587
249
1135
268
301
595
369
74
294
809
809
305
217
51
279
135
262
369
83
480
12
301
117
149
75
337
118
100
698
570
154
Phenotype
Obesity
BMI (in women)
Ilpodystrophy, leptin, leptin:BMI ratio
Leptin, BMI, waist-to-hip ratio (in Canadian OjiCree)
Familial partial lipodystrophy
Body weight, BMI, waist circumference, skinfolds,
subscapular
BMI (in women)
Percent body fat, fat mass, BMI, change (in white
women)
BMI
BMI
Waist-to-hip ratio
BMI, percent body fat, fat-free mass, fat mass,
respiratory quotient (in normal-weight individuals,
in overweight individuals)
Leptin (in morbidly obese subjects)
BMI, percent body fat, fat-free mass, fat mass (in
females)
Obesity (in children and adolescents)
BMI, waist-to-hip ratio
BMI (in postmenopausal women with breast cancer)
BMI, waist-to-hip ratio
Body weight at birth
Obesity (in Pima Indians)
Birth weight
BMI (in 7-year-olds)
Waist circumference (in 7-year-olds)
BMI (in women)
Obesity, early-onset
Abdominal visceral fat (in lean subjects)
BMI (in obese subjects)
Waist-to-hip ratio (in males)
Leptin, BMI, waist-to-hip ratio, waist circumference
Overweight (in type 2 diabetics)
Increase in sum of skinfolds (in girls)
Abdominal visceral fat
Body weight, gain
BMI (in postmenopausal women with breast cancer)
Lipolysis in adipocytes (in obese women)
Weight loss (in women)
Leptin (in obese children)
Leptin (in Mexican Americans)
Leptin (in lean subjects)
Body weight at birth (in Trinidadian neonates and
South Asians)
BMI
Percent body fat
BMI (in type 2 diabetics)
p
References
0.002
0.012
0.05
0.05
(594)
(595)
(596)
(597)
0.0001
0.002
(598)
(599)
0.02
0.01
(479)
(600)
0.05
0.009
0.0011
0.0005
(601)
(104)
(104)
(602)
0.05
0.003
(133)
(603)
0.006
0.023
0.01
0.03
0.03
0.05
0.05
0.05
0.01
0.05
0.009
0.003
0.04
0.01
0.001
0.003
0.01
0.001
0.01
0.005
0.0008
0.006
0.03
0.001
0.003
0.05
(19)
(604)
(105)
(605)
(606)
(607)
(106)
(106)
(106)
(106)
(608)
(609)
(107)
(610)
(611)
(108)
(136)
(612)
(613)
(105)
(131)
(139)
(614)
(615)
(134)
(616)
0.023
0.028
0.02
(109)
(109)
(617)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
397
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 6. (continued)
Gene
PPARG
Location
3p25.2
Cases
(N)
921
333
973
422
752
869
464
619
451
451
451
228
119
225
838
820
183
183
70
121
714
596
685
501
501
268
375
141
PPARGC1
4p15.31
RETN
SAH
SCARB1
19p13.3
16p13.11
12q24.31
SERPINE1
SLC6A3
SORBS1
TCF1
TGFB1
7q22.1
5p15.33
10q24.1
12q24.31
19q13.31
TNF
6p21.3
398
467
467
467
467
201
165
165
411
4059
288
228
505
90
770
203
284
284
176
136
38
1351
378
1047
363
Phenotype
Leptin, BMI, waist circumference (in Mexican
Americans)
BMI (in the middle-aged)
BMI (in the elderly)
BMI
BMI, change (in obese men)
BMI, change (in lean men)
Obesity, BMI
BMI
BMI (in overweight blacks)
Waist-to-hip ratio (in overweight blacks)
Waist circumference (in overweight blacks)
Morbid obesity
Weight, increase, 10-year
Weight, decrease, 3-year
Body weight, BMI, waist circumference, height
Leptin (in obese subjects)
24-hour lipid oxidation
24-hour lipid balance
Weight, increase
BMI
BMI
Fat mass
Waist circumference
Abdominal visceral fat
Abdominal subcutaneous fat
BMI
Obesity, severe, with early onset
Body weight, BMI, fat mass, waist circumference,
lean body bass, hip circumference
Fat mass (in Austrian women)
BMI (in Austrian women)
Waist circumference (in Austrian women)
Hip circumference (in Austrian women)
Adipocyte size (in Pima Indians)
24-hour lipid oxidation (in Pima Indians)
24-hour lipid balance (in Pima Indians)
Obesity, BMI
BMI
BMI (in healthy lean women)
Morbid obesity
Obesity
Obesity (in black smokers)
Obesity
BMI (in young early onset diabetics)
BMI (in Swedish men)
Abdominal sagittal diameter (in Swedish men)
BMI
Waist circumference (in women)
Percent body fat
BMI
BMI, percent body fat (in women)
Obesity
BMI
OBESITY RESEARCH Vol. 12 No. 3 March 2004
p
References
0.02
(618)
0.03
0.02
0.03
0.002
0.008
0.01
0.04
0.02
0.01
0.004
0.02
0.009
0.04
0.002
0.001
0.03
0.02
0.01
0.03
0.04
0.009
0.03
0.01
0.001
0.022
0.05
0.002
(619)
(619)
(111)
(620)
(620)
(621)
(622)
(114)
(114)
(114)
(112)
(623)
(624)
(625)
(626)
(129)
(129)
(627)
(628)
(113)
(113)
(113)
(113)
(113)
(110)
(629)
(630)
0.005
0.006
0.01
0.03
0.04
0.03
0.004
0.0097
0.0066
0.004
0.002
0.002
0.006
0.05
0.0024
0.05
0.05
0.01
0.04
0.02
0.004
0.02
0.04
0.01
(631)
(631)
(631)
(631)
(117)
(117)
(117)
(632)
(633)
(634)
(112)
(635)
(115)
(636)
(116)
(117)
(117)
(637)
(638)
(639)
(640)
(641)
(642)
(643)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 6. (continued)
Gene
Location
TNFRSF1B
TNRC11
UCP1
1p36.21
Xq13.1
4q31.1
UCP2
11q13.3
Cases
(N)
110
217
68
163
526
162
113
99
123
24
60
220
791
596
813
949
41
82
105
UCP3
11q13.3
120
116
419
73
734
393
401
382
64
Phenotype
p
References
Obesity
Leptin, BMI
Obesity
Body weight, decrease, BMI, decrease
BMI (in overweight women)
Waist-to-hip ratio
Body weight (in Japanese women)
Change in body weight (in premenopausal women)
Fat, increase (in high weight gainers)
Body weight, resting metabolic rate
Energy expenditure, 24-hour, spontaneous physical
activity, 24-hour, sleeping spontaneous physical
activity, respiratory quotient, 24-hour non-protein,
fat oxidation, 24-hour
BMI (in South Indian women)
BMI
Obesity
Obesity
Obesity
Body weight, increase, fat mass, increase (in
peritoneal dialysis patients)
BMI, metabolic rate, 24-hour sleeping (in those ⬎45
years old)
Body weight, BMI, percent body fat, fat mass,
overweight, percentage, skinfolds, sum of 4
BMI, respiratory quotient, lean body bass, nonprotein respiratory quotient, fat oxidation (in
African Americans)
Waist-to-hip ratio (in South Indian women, in
European women)
BMI
Resting energy expenditure (in black women)
leptin, BMI, percent body fat, fat mass, skinfolds,
sum of 6
skinfolds, sum of 8
BMI (in morbidly obese subjects)
Body weight, BMI, current, BMI, maximum
Leptin, percent body fat (in women)
0.02
0.05
0.001
0.05
0.02
0.003
0.001
0.048
0.05
0.05
0.005
(644)
(645)
(646)
(647)
(648)
(125)
(649)
(135)
(650)
(651)
(652)
0.02
0.03
0.007
0.002
0.006
0.05
(653)
(654)
(654)
(655)
(656)
(657)
0.007
(658)
0.001
(659)
0.008
(660)
0.03
(661)
0.004
0.01
0.0005
(662)
(663)
(664)
0.01
0.0037
0.02
0.03
(665)
(666)
(667)
(668)
Status as of October 2003.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
399
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. Evidence for the presence of linkage with obesity-related phenotypes in human studies
Gene/Marker
Location
D1S468
1p36.32
D1S508
1p36.23-22
PGD
D1S552
D1S3721
1p36.22
1p36.13
1p34.1
D1S193
D1S197
1p34.1
1p33
157
7
202
202
D1S200
D1S476
1p32.2
1p32.2
202 to 251 pairs
202 to 251 pairs
LEPR
1p31.3
302 subjects;
57 families
302 subjects;
57 families
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
268 to 324 pairs
198 subjects
236 pairs
LEPR-IVS16CTTT
1p31.3
LEPR-IVS3CA
1p31.3
LEPR-Q223R
1p31.3
D1S1665
D1S550
1p31.1
1p31.1
D1S534
1p11.2
D1S1679
1q21-22
ATP1A2
1q23.1
D1S476
1p32.2
ATP1B1
ACP1
1q23.3
2p25
D2S2337
D2S165
2p24.1
2p23.3
400
p or Lod
score
References
BMI
BMI
BMI
BMI
BMI
Skinfolds, suprailiac
BMI (in whites)
BMI (in whites)
Lod ⫽ 2.75
MLS ⫽ 2.09
Lod ⫽ 2.5
Lod ⫽ 2.5
Lod ⫽ 2.5
p ⫽ 0.03
p ⫽ 0.002
p ⫽ 0.0099
(669)
(669)
(670)
(670)
(670)
(671)
(182)
(184)
BMI (Quebec Family Study)
Insulin level, fasting (Quebec Family
Study)
Fat mass (Quebec Family Study)
Insulin level, integrated, following
oral glucose tolerance test (Quebec
Family Study)
Blood glucose, fasting (in Mexican
Americans)
Blood pressure, diastolic (in Mexican
Americans)
Fat-free mass
Fat mass
BMI
Fat-free mass
Fat mass
Skinfolds, sum of 6
Fat mass
BMI
Skinfolds, sum of 6
Fat-free mass
Leptin
Respiratory quotient, 24-hour (in Pima
Indians)
BMI (in Africans)
p ⫽ 0.03
p ⫽ 0.05
(672)
(672)
p ⫽ 0.009
p ⫽ 0.02
(672)
(672)
p ⫽ 0.018
(673)
p ⫽ 0.003
(673)
p ⫽ 0.007
p ⫽ 0.05
p ⫽ 0.05
p ⫽ 0.05
p ⫽ 0.05
p ⫽ 0.05
p ⫽ 0.005
p ⫽ 0.02
p ⫽ 0.02
p ⫽ 0.02
Lod ⫽ 3.4
Lod ⫽ 2.8
(581)
(581)
(581)
(581)
(581)
(581)
(581)
(581)
(581)
(581)
(674)
(675)
Lod ⫽ 2.24
(181)
Abdominal subcutaneous fat (Quebec
Family Study)
BMI (National Heart, Lung and Blood
Institute Family Heart Study)
Respiratory quotient (Quebec Family
Study)
Adipocyte size
Lod ⫽ 2.3
(676)
Lod ⫽ 1.8
(677)
p ⫽ 0.02
(518)
Lod ⫽ 1.7
(678)
Insulin level, integrated, following
oral glucose tolerance test (Quebec
Family Study)
Respiratory quotient
BMI
Skinfolds, triceps
Leptin (in French Caucasians)
Adiponectin (in Northern Europeans)
p ⫽ 0.02
(672)
p ⫽ 0.04
p ⫽ 0.004
p ⫽ 0.02
Lod ⫽ 2
Lod ⫽ 2.7
(517)
(679)
(671)
(680)
(681)
Leptin
Lod ⫽ 2.4
(190)
Population
1249 sib pairs
1249 sib pairs
994 subjects
994 subjects
994 subjects
⬎168 pairs
subjects;
families
to 251 pairs
to 251 pairs
769 subjects;
182 families
521 subjects;
156 families
3027 subjects;
401 families
171 families;
289 pairs
295 subjects;
164 families
202 to 251 pairs
94 pairs
300 pairs
⬎168 pairs
1100 subjects;
170 families
264 pairs
OBESITY RESEARCH Vol. 12 No. 3 March 2004
Phenotypes
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
D2S367
2p23.1
D2S1788
2p22.3
D2S441
2p13.3
IGKC
D2S160
D2S347
2p11.2
2q13
2q14.3
D2S1334
2q21.3
D2S1399
2q23.3
D2S434
2q35
D3S2387
3p26.3
D3S1259
D3S3038
D3S2432
3p25.2
3p24.3
3p22.3
D3S1768
D3S1764
D3S2427
3p22.2
3q22.3
3q26.33
D3S3676
3q26.33
D3S1311
3q29
D4S2397
4p15.2
p or Lod
score
References
Adiponectin (in Northern Europeans)
Lod ⫽ 2.7
(681)
Leptin
Leptin
Fat mass
Leptin
BMI (in whites)
Leptin
Lod ⫽ 2.7
Lod ⫽ 4.9
Lod ⫽ 2.8
Lod ⫽ 7.5
Lod ⫽ 3.08
p ⫽ 0.008
(190)
(189)
(189)
(615)
(183)
(682)
BMI
p ⫽ 0.008
(682)
Abdominal subcutaneous fat
Lod ⫽ 1.9
(683)
Skinfolds, triceps
BMI
BMI
Body fat, percentage
Fat mass
BMI
Abdominal visceral fat
p ⫽ 0.03
Lod ⫽ 2.56
Lod ⫽ 4.04
Lod ⫽ 1.91
Lod ⫽ 2.03
MLS ⫽ 4.44
Lod ⫽ 2.3
(671)
(669)
(669)
(669)
(669)
(669)
(683)
Abdominal visceral fat
Lod ⫽ 2.3
(683)
Abdominal visceral fat
Lod ⫽ 2.5
(683)
Abdominal subcutaneous fat
Lod ⫽ 2.2
(683)
BMI
BMI, paternal effect (in whites)
Body fat, percentage (in Pima
Indians)
BMI
BMI
BMI
Lod ⫽ 2
p ⫽ 0.0065
Lod ⫽ 2
(684)
(182)
(685)
Lod ⫽ 3.4
Lod ⫽ 3.4
Lod ⫽ 3.3
(684)
(191)
Waist circumference
Lod ⫽ 2.4
(191)
BMI (in African Americans)
Lod ⫽ 2.4
(185)
BMI (in African Americans)
Lod ⫽ 4.3
(185)
BMI
BMI
Lod ⫽ 3.4
Lod ⫽ 1.8
(684)
(686)
BMI (in African Americans)
Lod ⫽ 4.3
(185)
Abdominal subcutaneous fat
Lod ⫽ 2.5
(683)
Abdominal subcutaneous fat (Quebec
Family Study)
Lod ⫽ 2.4
(676)
Population
1100 subjects;
170 families
264 pairs
337 subjects
349 subjects
720 subjects;
230 families
720 subjects;
230 families
668 subjects;
99 families
⬎168 pairs
1249 sib pairs
1249 sib pairs
1249 sib pairs
1249 sib pairs
1249 sib pairs
668 subjects;
99 families
668 subjects;
99 families
668 subjects;
99 families
668 subjects;
99 families
1055 pairs
377 pairs
580 families
1055 pairs
2209 subjects;
507 families
2209 subjects;
507 families
545 subjects;
128 families
545 subjects;
128 families
1055 pairs
618 subjects;
202 families
545 subjects;
128 families
668 subjects;
99 families
521 subjects;
156 families
Phenotypes
OBESITY RESEARCH Vol. 12 No. 3 March 2004
401
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
D4S3350
4p15.1
D4S2632
4p15.1
D4S1592
D4S2417
4q12
4q31.1
GYPA
D4S1629
D4S2431
4q31.1
4q32.1
4q34.1
D5S817
5p15.2
Population
994
994
994
994
994
subjects
subjects
subjects
subjects
subjects
1249 sib pairs
521 subjects;
156 families
160 pairs
668 subjects;
99 families
1100 subjects;
170 families
618 subjects;
202 families
264 pairs
1526 pairs
226 pairs
226 pairs
226 pairs
1249 sib pairs
1526 pairs
668 subjects;
99 families
88 pairs
668 subjects;
99 families
D5S426
D5S2489
ISL1
5p13.3
5p13.2
5q11.2
D5S407
D5S2500
D5S658
5q11.2
5q12.1
5q31.3
NR3C1
D5S1480
5q31
5q32
D5S1471
D5S211
5q35.1
5q35.2
D5S408
5q35.3
D6S1959
6p22.3-2
D6S276
6p22.1
TNF
6p21.3
BF
6p21.31
GLO1
6p21.2
D6S271
D6S403
6p21.1
6q23.3
⬎168 pairs
⬎168 pairs
⬎168 pairs
⬎168 pairs
⬎168 pairs
1199 pairs
261 subjects
D6S1003
6q24.1
261 subjects
402
3027 subjects;
401 families
157 subjects;
7 families
618 subjects;
202 families
624 subjects;
28 families
⬎255 pairs
OBESITY RESEARCH Vol. 12 No. 3 March 2004
Phenotypes
p or Lod
score
References
Lod ⫽ 9.2
p ⫽ 11.3
MLS ⫽ 9.2
p ⫽ 5.3
MLS ⫽ 6.1
HLOD
Lod ⫽ 2.29
p ⫽ 0.005
Lod ⫽ 1.8
(670)
(670)
(670)
(670)
(670)
p ⫽ 0.02
p ⫽ 0.005
Lod ⫽ 2.3
(687)
(182)
(683)
Adiponectin (in Northern Europeans)
Lod ⫽ 4.1
(681)
BMI
Lod ⫽ 1.9
(686)
Leptin
BMI (in Pima Indians)
Obesity
Leptin
BMI
Fat-free mass
BMI (in Pima Indians)
Abdominal subcutaneous fat
Lod ⫽ 2.9
Lod ⫽ 1.7
p ⫽ 0.03
p ⫽ 0.0004
p ⫽ 0.0004
Lod ⫽ 1.59
Lod ⫽ 1.7
Lod ⫽ 2.1
(190)
(688)
(689)
(689)
(689)
(669)
(688)
(683)
BMI
Abdominal total fat
p ⫽ 0.009
Lod ⫽ 2.1
(689)
(683)
BMI (in whites)
BMI (National Heart, Lung and Blood
Institute Family Heart Study)
BMI (in whites)
p ⫽ 0.0006
Lod ⫽ 1.8
(182)
(677)
p ⫽ 0.0039
(184)
Body fat, percentage
Lod ⫽ 2.7
(686)
Eating behavior, restraint (in Old
Order Amish)
Body fat, percentage (in Pima
Indians)
Skinfolds, subscapular
Skinfolds, triceps
Skinfolds, suprailiac
Body weight
Skinfolds, suprailiac
Leptin
(BMI, leptin, FSI) (in Mexican
Americans)
(BMI, leptin, FSI) (in Mexican
Americans)
Lod ⫽ 2.3
(690)
p ⫽ 0.002
(643)
p ⫽ 0.01
p ⫽ 0.01
p ⫽ 0.01
p ⫽ 0.004
p ⫽ 0.004
Lod ⫽ 2.1
Lod ⫽ 4.2
(671)
(671)
(671)
(671)
(671)
(691)
(692)
Lod ⫽ 4.2
(692)
BMI
BMI
BMI
BMI
BMI
BMI
BMI, paternal effect (in whites)
Abdominal subcutaneous fat (Quebec
Family Study)
Skinfolds, trunk to extremity ratio
BMI, maternal effect (in whites)
Abdominal subcutaneous fat
(669)
(182)
(676)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
Population
D6S264
6q27
261 subjects
D6S281
6q27
D7S2477
D7S1819
D7S3051
NPY
7p22.3
7p22.2
7p21.1
7p15.3
1249 sib pairs
1249 sib pairs
349 subjects
349 subjects
1055 pairs
302 subjects;
57 families
302 subjects;
57 families
302 subjects;
57 families
302 subjects;
57 families
302 subjects;
57 families
302 subjects;
57 families
D7S1808
D7S817
7p15.1
7p14.3
D7S479
7q22.1
D7S692
7q22.3
D7S523
7q31.1
D7S471
7q31.1
D7S2847
D7S680
D7S514
7q31.31
7q32.2
7q32.2
769 subjects;
182 families
261 subjects
1020 subjects;
200 families
1020 subjects;
200 families
261 subjects
1055 pairs
60 pairs
60 pairs
545 pairs
545 pairs
545 pairs
D7S504
7q32.2
D7S1875
7q32.2
LEP
7q32.2
545 pairs
46 pairs
59 pairs
302 subjects;
57 families
521 subjects;
156 families
88 pairs
302 subjects;
57 families
302 subjects;
57 families
302 subjects;
57 families
p or Lod
score
References
(Systolic and diastolic blood pressure)
(in Mexican Americans)
BMI
Fat mass
BMI (in whites)
BMI (in whites)
BMI
Obesity (in Mexican Americans)
Lod ⫽ 4.9
(692)
Lod ⫽ 1.77
Lod ⫽ 2.02
Lod ⫽ 2.53
Lod ⫽ 2.53
Lod ⫽ 2.7
p ⫽ 0.042
(669)
(669)
(183)
(183)
(684)
(673)
Body weight (in Mexican Americans)
p ⫽ 0.02
(673)
Abdominal circumference (in Mexican
Americans)
Hip circumference (in Mexican
Americans)
Blood pressure, diastolic (in Mexican
Americans)
(Body mass, body size) (in Mexican
Americans)
Fat-free mass (Quebec Family Study)
BMI (in Africans)
p ⫽ 0.031
(673)
p ⫽ 0.012
(673)
p ⫽ 0.005
(673)
p ⫽ 0.048
(673)
Lod ⫽ 2.72
Lod ⫽ 3.83
(693)
(181)
(HDL, ln-TG) (in Mexican
Americans)
BMI (in whites)
Lod ⫽ 3.2
(692)
p ⫽ 0.0002
(186)
BMI (in whites)
p ⫽ 0.0009
(186)
(HDL, ln-TG) (in Mexican
Americans)
BMI
BMI
BMI
BMI (in Mexican Americans)
Skinfolds, extremity (in Mexican
Americans)
Waist circumference (in Mexican
Americans)
Fat mass (in Mexican Americans)
BMI (in African Americans)
BMI
Waist-to-hip ratio (in Mexican
Americans)
Abdominal subcutaneous fat (Quebec
Family Study)
BMI
Waist-to-hip ratio (in Mexican
Americans)
Cholesterol, total (in Mexican
Americans)
Cholesterol, HDL (in Mexican
Americans)
Lod ⫽ 3.2
(692)
Lod ⫽ 2.4
p ⫽ 0.002
p ⫽ 0.002
p ⫽ 0.0001
p ⫽ 0.0001
(684)
(694)
(694)
(695)
(695)
p ⫽ 0.0001
(695)
p ⫽ 0.0001
p ⫽ 0.001
p ⫽ 0.04
p ⫽ 0.009
(695)
(696)
(697)
(673)
Lod ⫽ 2
(676)
p ⫽ 0.04
p ⫽ 0.01
(698)
(673)
p ⫽ 0.03
(673)
p ⫽ 0.026
(673)
Phenotypes
OBESITY RESEARCH Vol. 12 No. 3 March 2004
403
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
D7S530
D7S1804
D7S640
D7S495
Location
7q32.3
7q32.3
7q33
7q34
Population
47 pairs
60 pairs
3027 subjects;
401 families
3027 subjects;
401 families
672 subjects
545 pairs
545 pairs
545 pairs
545 pairs
D7S1824
7q34
KEL
7q35
D7S2195
7q35
D7S3068
7q35
D7S636
D7S3070
7q36.1
7q36.2
D8S277
GATA151F02
8p23.1
8p22
D8S549
D8S282
D8S1121
D8S1110
D8S1113
D8S556
8p22
8p21.3
8p11.23
8q11.22
8q12.1
8q23.1
D8S1132
8q23.1
D9S1122
9q21.32
D9S257
9q22.1
ORM1
AK1
D9S158
9q33.1
9q34.13
9q34.3
D10S1435
10p15.3
D10S189
404
10p15.1
157 subjects;
7 families
160 pairs
160 pairs
157 subjects;
7 families
157 subjects;
7 families
672 subjects
668 subjects;
99 families
769 subjects;
182 families
1249 sib pairs
994 subjects
470 subjects
522 subjects;
99 families
157 subjects;
7 families
521 subjects;
156 families
521 subjects;
156 families
⬎168 pairs
⬎168 pairs
522 subjects;
99 families
522 subjects;
99 families
522 subjects;
99 families
1526 pairs
522 subjects;
99 families
OBESITY RESEARCH Vol. 12 No. 3 March 2004
Phenotypes
p or Lod
score
References
Body fat
BMI
BMI (National Heart, Lung and Blood
Institute Family Heart Study)
BMI (National Heart, Lung and Blood
Institute Family Heart Study)
Leptin (in Old Order Amish)
BMI (in Mexican Americans)
Skinfolds, extremity (in Mexican
Americans)
Fat mass (in Mexican Americans)
Waist circumference (in Mexican
Americans)
BMI (in whites)
p ⫽ 0.008
p ⫽ 0.002
MLS ⫽ 4.7
p ⬍ 0.00001
MLS ⫽ 3.2
p ⬍ 0.00007
p ⫽ 1.9
p ⫽ 0.0001
p ⫽ 0.0001
(699)
(694)
(677)
p ⫽ 0.0001
p ⫽ 0.0001
(695)
(695)
p ⫽ 0.0008
(184)
BMI
Skinfolds, sum of 6
BMI (in whites)
p ⫽ 0.0001
p ⫽ 0.0001
p ⫽ 0.001
(687)
(687)
(184)
BMI (in whites)
p ⫽ 0.004
(184)
Leptin (in Old Order Amish)
Abdominal total fat
p ⫽ 1.9
Lod ⫽ 2.5
(700)
(683)
BMI, paternal effect (in whites)
BMI (in Africans)
p ⫽ 0.003
Lod ⫽ 2.34
(182)
(181)
Fat mass
BMI
BMI (in Mexican Americans)
Leptin
BMI (in whites)
BMI (HERITAGE, in whites)
Lod ⫽ 1.95
Lod ⫽ 2
Lod ⫽ 3.2
Lod ⫽ 2.2
p ⫽ 0.0013
Lod ⫽ 2
(669)
(670)
(701)
(189)
(182)
(702)
BMI (in whites)
p ⫽ 0.005
(184)
Abdominal subcutaneous fat (Quebec
Family Study)
Abdominal subcutaneous fat (Quebec
Family Study)
Skinfolds, suprailiac
Skinfolds, suprailiac
BMI (HERITAGE, in whites)
Lod ⫽ 2.4
(676)
Lod ⫽ 2.4
(676)
p ⫽ 0.03
p ⫽ 0.01
Lod ⫽ 2.3
(671)
(671)
(702)
BMI (HERITAGE, in whites)
Lod ⫽ 2.7
(702)
Fat mass (HERITAGE, in whites)
Lod ⫽ 2.7
(702)
BMI (in Pima Indians)
BMI (HERITAGE, in whites)
Lod ⫽ 1.7
MLS ⫽ 2.7
SEGPATH
(688)
(702)
(677)
(700)
(695)
(695)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
D10S1781
10p13-q11
D10S1423
D10S582
10p12.33
10p12.31
D10S197
10p12.2
D10S204
10p12.1
D10S193
10p12.1
D10S208
10p11.23
SHGC-31480
10p11.23
D10S220
D10S107
10q21.1
10q21.1
D10S1646
10q22.1
D10S535
D10S1679
D10S1656
10q22.3
10q26.13
10q26.2
D10S212
CCKBR
C11P15_3
10q26.3
11p15.4
11p15.2
D11S419
ATA34E08
11p15.2
11p14.1
D11S1313
11q12.1
Population
522 subjects;
99 families
522 subjects;
99 families
1526 pairs
386 subjects;
93 families
667 subjects;
244 families
862 subjects;
170 families
264 pairs
369 subjects;
89 families
386 subjects;
93 families
386 subjects;
93 families
667 subjects;
244 families
862 subjects;
170 families
386 subjects;
93 families
672 subjects
862 subjects;
170 families
667 subjects;
244 families
667 subjects;
244 families
667 subjects;
244 families
667 subjects;
244 families
667 subjects;
244 families
667 subjects;
244 families
667 subjects;
244 families
667 subjects;
244 families
198 subjects
226 pairs
668 subjects;
99 families
67 pairs
668 subjects;
99 families
369 subjects;
89 families
Phenotypes
p or Lod
score
References
MLS ⫽ 2.3
Mapmaker/Sibs
MLS ⫽ 1
Mapmaker/Sibs
Lod ⫽ 1.7
Lod ⫽ 2.5
(702)
BMI, paternal effect (in whites)
Obesity (in whites and African
Americans)
Obesity
p ⫽ 0.005
NPL ⫽ 2.68
(182)
(187)
Obesity
Obesity (in white children and
adolescents)
Obesity
Lod ⫽ 4.9
Lod ⫽ 2.24
(190)
(188)
Lod ⫽ 2.5
(703)
Obesity
Lod ⫽ 2.5
(703)
Obesity (in whites and African
Americans)
Obesity
NPL ⫽ 2.68
(187)
Obesity
Lod ⫽ 2.5
(703)
Leptin (in Old Order Amish)
Obesity
Lod ⫽ 2.7
p ⫽ 0.0005
(700)
(704)
Waist circumference (in whites and
African Americans)
BMI (in whites and African
Americans)
Waist circumference (in whites and
African Americans)
BMI (in whites and African
Americans)
Waist-to-hip ratio (in whites and
African Americans)
Obesity (in whites and African
Americans)
Waist-to-hip ratio (in whites and
African Americans)
Obesity (in whites and African
Americans)
BMI
Leptin
Abdominal subcutaneous fat
Lod ⫽ 2.5
(187)
NPL ⫽ 2.24
(187)
Lod ⫽ 2.5
(187)
NPL ⫽ 2.24
(187)
NPL ⫽ 2.22
(187)
NPL ⫽ 2.25
(187)
NPL ⫽ 2.22
(187)
NPL ⫽ 2.25
(187)
Lod ⫽ 3.3
p ⫽ 0.01
Lod ⫽ 1.9
(674)
(689)
(683)
BMI (in French Caucasians)
Abdominal subcutaneous fat
p ⫽ 0.003
Lod ⫽ 1.8
(453)
(683)
Obesity (in white children and
adolescents)
Lod ⫽ 1.65
(188)
BMI (HERITAGE, in whites)
Fat mass (HERITAGE, in whites)
BMI (in Pima Indians)
Obesity
p ⫽ 0.0005
p ⫽ 0.0005
(702)
(688)
(703)
(704)
(704)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
Population
D11S916
11q13.3
640 subjects
D11S1321
11q13.3
640 subjects
640 subjects
D11S911
11q13.4
D11S2000
11q22.3
D11S2366
11q23.1
640 subjects
640 subjects
769 subjects;
182 families
377 pairs
157 subjects;
7 families
377 pairs
377 pairs
D11S1998
D11S976
11q23.3
11q23.3
1526 pairs
236 pairs
D11S4464
11q24.1
D11S934
D11S912
11q24.2
11q24.3
1526 pairs
994 subjects
994 subjects
1766 pairs
994 subjects
D3S2395
D12S1042
12p13.31
12p12.1
D12S1045
D12S83
D12S1052
D12S1064
IGF1
12p11.23q13.12
12q13.3
12q21.1
12q21.33
12q23.3
D12S2078
12q24.32
D13S175
D13S221
ESD
13q12.11
13q12.13
13q14.11
D13S257
13q14.2
D13S285
13q34
D14S742
14q11.2
406
522 subjects;
99 families
522 subjects;
99 families
521 subjects;
156 families
1249 sib pairs
349 subjects
349 subjects
521 subjects;
156 families
352 pairs
521 subjects;
156 families
580 families
580 families
160 pairs
160 pairs
3027 subjects;
401 families
521 subjects;
156 families
522 subjects;
99 families
OBESITY RESEARCH Vol. 12 No. 3 March 2004
Phenotypes
p or Lod
score
References
p ⫽ 0.006
(705)
p ⫽ 0.02
(705)
p ⫽ 0.04
(705)
p ⫽ 0.02
p ⫽ 0.000002
(705)
(705)
Lod ⫽ 3.35
(181)
Body fat, percentage (in Pima
Indians)
BMI (in whites)
Lod ⫽ 2.8
(685)
p ⫽ 0.0079
(184)
Body fat, percentage (in Pima
Indians)
Body fat, percentage (in Pima
Indians)
BMI (in Pima Indians)
Energy expenditure, 24-hour (in Pima
Indians)
BMI (in Pima Indians)
BMI
BMI
BMI
BMI
BMI, paternal effect (in whites)
BMI (HERITAGE, in whites)
p ⫽ 2.1
(685)
p ⫽ 2.8
(685)
Lod ⫽ 2.7
Lod ⫽ 2
(688)
(675)
Lod ⫽ 2.7
Lod ⫽ 2.8
Lod ⫽ 2.8
Lod ⫽ 3.6
Lod ⫽ 2.8
p ⫽ 0.006
MLS ⫽ 2.1
Mapmaker/Sibs
MLS ⫽ 1.2
SEGPATH
Lod ⫽ 2.9
(688)
(670)
(670)
(706)
(670)
(182)
(702)
Lod ⫽ 1.79
Lod ⫽ 3.41
Lod ⫽ 3.41
Lod ⫽ 1.9
(669)
(183)
(183)
(676)
p ⫽ 0.02
Lod ⫽ 2.9
(556)
(676)
Lod ⫽ 3.3
Lod ⫽ 3.3
p ⫽ 0.04
p ⫽ 0.04
MLS ⫽ 3.2
p ⬍ 0.00006
Lod ⫽ 1.9
(687)
(687)
(677)
Resting metabolic rate (Quebec
Family Study)
Resting metabolic rate (Quebec
Family Study)
Body fat, percentage (Quebec Family
Study)
Fat mass (Quebec Family Study)
Resting metabolic rate (Quebec
Family Study)
BMI (in Africans)
Fat mass (HERITAGE, in whites)
Abdominal subcutaneous fat (Quebec
Family Study)
Fat-free mass
BMI (in whites)
BMI (in whites)
Abdominal subcutaneous fat (Quebec
Family Study)
Abdominal visceral fat
Abdominal subcutaneous fat (Quebec
Family Study)
BMI
BMI
Body fat, percentage
Skinfolds, sum of 6
BMI (National Heart, Lung and Blood
Institute Family Heart Study)
Abdominal subcutaneous fat (Quebec
Family Study)
Fat mass (HERITAGE, in whites)
MLS ⫽ 1.7
Mapmaker/Sibs
(702)
(676)
(676)
(702)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
Population
522 subjects;
99 families
D14S283
D14S1280
14q11.2
14q11.2
D14S608
14q12
D14S599
14q13.1
D14S276
14q22.2
D14S588
14q24.1
D14S74
D14S280
D14S617
D15S1232
14q24.3
14q32.12
14q32.12
15q13.3
D15S652
D15S657
D16S510
15q26.1
15q26.2
16p13.3
D16S404
D16S764
D16S2620
D16S265
D17S947
16p13.2
16p13.12
16q21
16q21
17p12
D17S2180
17q21.32
D17S1290
17q23.2
D17S1301
17q25.2
MC5R
18p11.21
522 subjects;
99 families
522 subjects;
99 families
522 subjects;
99 families
522 subjects;
99 families
522 subjects;
99 families
522 subjects;
99 families
1100 subjects;
170 families
1100 subjects;
170 families
672 subjects
668 subjects;
99 families
672 subjects
672 subjects
1055 pairs
3027 subjects;
401 families
672 subjects
672 subjects
1055 pairs
1199 pairs
1100 subjects;
170 families
2209 subjects;
507 families
1055 pairs
521 subjects;
156 families
521 subjects;
156 families
521 subjects;
156 families
289 pairs
289 pairs
Phenotypes
p or Lod
score
References
(702)
BMI (in whites)
Fat mass (HERITAGE, in whites)
MLS ⫽ 2.2
SEGPATH
p ⫽ 0.002
p ⫽ 0.0006
Leptin (HERITAGE, in whites)
p ⫽ 0.003
(702)
Fat mass (HERITAGE, in whites)
(702)
Adiponectin (in Northern Europeans)
MLS ⫽ 2
Mapmaker/Sibs
MLS ⫽ 1.8
SEGPATH
MLS ⫽ 1.1
SEGPATH
MLS ⫽ 2.4
SEGPATH
Lod ⫽ 3.2
Adiponectin (in Northern Europeans)
Lod ⫽ 3.2
(681)
Waist circumference (in Old Order
Amish)
Abdominal subcutaneous fat
Lod ⫽ 1.8
(700)
Lod ⫽ 2.4
(683)
Leptin (in Old Order Amish)
Leptin (in Old Order Amish)
BMI
BMI (National Heart, Lung and Blood
Institute Family Heart Study)
Fat-free mass (Quebec Family Study)
Fat-free mass (Quebec Family Study)
Leptin (in Old Order Amish)
BMI (in Old Order Amish)
BMI (in whites)
BMI (in whites)
BMI
Leptin
Adiponectin (in Northern Europeans)
Lod ⫽ 2.5
Lod ⫽ 2.5
Lod ⫽ 2.2
Lod ⫽ 1.7
(700)
(700)
(684)
(677)
Lod ⫽ 3.56
Lod ⫽ 2
Lod ⫽ 1.7
Lod ⫽ 1.7
p ⫽ 0.00025
p ⫽ 0.0006
Lod ⫽ 2.6
Lod ⫽ 2
Lod ⫽ 1.7
(693)
(693)
(700)
(700)
(182)
(182)
(684)
(691)
(681)
Leptin
Lod ⫽ 5
(191)
BMI
Abdominal subcutaneous fat (Quebec
Family Study)
Abdominal subcutaneous fat (Quebec
Family Study)
Abdominal subcutaneous fat (Quebec
Family Study)
BMI (Quebec Family Study)
Skinfolds, sum of 6 (Quebec Family
Study)
Lod ⫽ 2.5
Lod ⫽ 2.2
(684)
(676)
Lod ⫽ 2.2
(676)
Lod ⫽ 2.2
(676)
p ⫽ 0.001
p ⫽ 0.005
(603)
(603)
BMI (HERITAGE, in whites)
BMI (HERITAGE, in whites)
Fat-free mass (HERITAGE, in whites)
BMI (HERITAGE, in whites)
(182)
(702)
(702)
(702)
(702)
(681)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
407
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
Population
289 pairs
289 pairs
289 pairs
289 pairs
D18S877
18q12.1
236 pairs
D18S535
D18S1155
MC4R
18q12.3
18q21.32
18q21.32
LDLR
19p13.2
D19S414
19q13.11
D20S482
D20S851
D20S601
D20S478
D20S438
20p13
20p12.3
20q11.22q11.23
20q12
20q12
D20S465
D20S107
20q12
20q12
ADA
20q13.12
D20S481
D20S17
20q13.12
20q13.12
D20S178
20q13.13
D20S211
20q13.2
D20S120
408
20q13.2
193 pairs
289 pairs
522 subjects;
99 families
522 subjects;
99 families
522 subjects;
99 families
369 subjects;
89 families
236 pairs
994 subjects
1711 subjects
994 subjects
994 subjects
513 subjects;
92 families;
423 pairs
513 subjects;
92 families;
423 pairs
160 pairs
160 pairs
994 subjects
650 subjects;
139 to 226 pairs
667 subjects;
244 families
513 subjects;
92 families;
423 pairs
513 subjects;
92 families;
423 pairs
650 subjects;
139 to 226 pairs
OBESITY RESEARCH Vol. 12 No. 3 March 2004
Phenotypes
p or Lod
score
References
Fat mass (Quebec Family Study)
Body fat, percentage (Quebec Family
Study)
Fat-free mass (Quebec Family Study)
Resting metabolic rate (Quebec
Family Study)
Fat-free mass (Quebec Family Study)
Body fat, percentage (in Pima
Indians)
Fat-free mass (Quebec Family Study)
Obesity (in Finns)
Respiratory quotient (Quebec Family
Study)
Skinfolds, sum of 8 (HERITAGE, in
whites)
Leptin (HERITAGE, in whites)
p ⫽ 0.001
p ⫽ 0.02
(603)
(603)
p ⫽ 0.008
p ⫽ 0.002
(603)
(603)
Lod ⫽ 3.6
Lod ⫽ 2.3
(693)
(675)
Lod ⫽ 3.58
Lod ⫽ 2.4
p ⫽ 0.04
(693)
(707)
(603)
p ⫽ 0.002
(702)
p ⫽ 0.0009
(702)
Body fat, percentage (HERITAGE, in
whites)
Obesity (in white children and
adolescents)
BMI (in whites)
BMI (in whites)
Respiratory quotient, 24-hour (in Pima
Indians)
BMI
BMI (in Utah pedigrees)
BMI
BMI
BMI
p ⫽ 0.009
(702)
Lod ⫽ 1.97
(188)
p ⫽ 0.00016
p ⫽ 0.000046
Lod ⫽ 3
(182)
(182)
(675)
Lod ⫽ 2.2
Lod ⫽ 3.5
Lod ⫽ 2.2
Lod ⫽ 2.2
Lod ⫽ 3.2
(670)
(708)
(670)
(670)
(709)
Body fat, percentage
Lod ⫽ 3.2
(709)
BMI
Skinfolds, sum of 6
BMI
Body fat, percentage
p ⫽ 0.001
p ⫽ 0.001
Lod ⫽ 2.2
p ⫽ 0.0078
(687)
(687)
(670)
(410)
Body fat, percentage (in whites and
African Americans)
BMI
NPL ⫽ 2.57
(187)
Lod ⫽ 3.2
(709)
Body fat, percentage
Lod ⫽ 3.2
(709)
Body fat, percentage
p ⫽ 0.004
(410)
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Table 7. (continued)
Gene/Marker
Location
D20S476
20q13
D20S149
20q13.31-qter
D3S3608
20q13.33
D22S264
22q11.21
A4GALT
DXS8099
DXS997
22q13.31
Xp22.13
Xp21.3
DXS1003
Xp11.3
DXS1059
DXS6804
Xq23
Xq23
p or Lod
score
References
BMI
Lod ⫽ 3.06
(709)
Body fat, percentage (in whites and
African Americans)
BMI
NPL ⫽ 2.57
(187)
Lod ⫽ 3.2
(709)
Body fat, percentage
Lod ⫽ 3.2
(709)
Eating behavior, restraint (in Old
Order Amish)
Abdominal subcutaneous fat
Lod ⫽ 2.5
(690)
Lod ⫽ 2
(683)
Body weight
BMI
Waist-to-hip ratio
p ⫽ 0.03
Lod ⫽ 2.6
Lod ⫽ 2.7
(671)
(670)
(710)
Waist-to-hip ratio
Lod ⫽ 2.7
(710)
BMI
Obesity (in Finns)
Lod ⫽ 2
Lod ⫽ 3.1
(670)
(707)
Population
513 subjects;
92 families;
423 pairs
667 subjects;
244 families
513 subjects;
92 families;
423 pairs
513 subjects;
92 families;
423 pairs
624 subjects;
28 families
668 subjects;
99 families
⬎168 pairs
994 subjects
208 subjects;
43 families
208 subjects;
43 families
994 subjects
193 pairs
Phenotypes
Status as of October 2003.
HDL, high-density lipoprotein; ln-TG, natural log-transformed triglycerides; MLS, multipoint Lod score; NPL, nonparametric linkage score.
Computer programs used: 1) SEGPATH [Province MA, Rao DC. General purpose model and a computer program for combined segregation and path
analysis (SEGPATH): automatically creating computer programs from symbolic language model specifications. Genet Epidemiol. 1995; 12:203–19; Province
MA, Rice TK, Borecki IB, Gu C, Kraja A, Rao DC. Multivariate and multilocus variance components method, based on structural relationships to assess
quantitative trait linkage via SEGPATH. Genet Epidemiol. 2003;24:128 –38]; and 2) MapMaker Sibs (Kruglyak L, Lander E. Complete multipoint sib pair
analysis of qualitative and quantitative traits. Am J Hum Genet. 1995;57:439 –54).
Table 8. Evolution in the status of the Human Obesity Gene Map
1994
Single-gene mutations*
KO and Tg
Mendelian disorders
with map location
Animal QTLs
Human QTLs from
genome scans
Candidate genes with
positive findings
8
7
9
1995
12
9
10
1996
13
24
13
1997
1998
1999
2000
2001
2002
2003
2
6
6
6
6
6
38
6/7
55
16
55
16
67
20
98
24
115
25
165
33
168
41
183
3
8
14
21
33
68
139
21
29
40
48
58
71
90
From Refs. 1–9 and this review.
* Number of genes, not number of mutations.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
409
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
that there are now 15 candidate genes that are supported by
a minimum of five independent association studies. Of
course, many of these loci on the map will turn out to be
more important than others, and many will eventually be
proven to be false positives. The main goals remain to
identify the combination of genes and mutations that are
contributing to the predisposition to human obesity and to
determine the environmental circumstances under which
these gene combinations and mutations occur.
Most of the advances to date have come from an understanding of the single-gene mutations that have the potential
to cause obesity in a small number of individuals. With the
developments in human and model organisms genome sequences and the progress in laboratory technologies, analytical tools, and bioinformatics, one can anticipate that it
will be possible to define the genes and mutations involved
in the predisposition or the resistance to obesity. It is likely
that the oligogenic cases in which a small number of genes
(digenic, trigenic, etc.) with large effects will be resolved
first. We hope that this publication will contribute to this
enormous challenge.
Acknowledgments
Our research on the genetics of obesity is funded by the
Canadian Institutes for Health Research (MOP-13960), the
Pennington Biomedical Research Center, and an unrestricted grant from Bristol-Myers Squibb. C.B. is supported
by the George A. Bray Chair in Nutrition. Our gratitude
goes to Nina Laidlaw for her help with the final version of
the paper. The list of genes and markers currently in the
map, as well as the pictorial representation of the map, is
also available online at http://obesitygene.pbrc.edu (Pennington Biomedical Research Center, Human Genomics
Laboratory) .
References
1. Bouchard C, Perusse L. Current status of the human obesity
gene map. Obes Res. 1996;4:81–90.
2. Perusse L, Bouchard C. Identification of genes contributing to
excess body fat and fat distribution. In: Angel A, Anderson H,
Bouchard C, Lau D, Leiter L Mendelson R, eds. 7th International Congress on Obesity. Progress in Obesity Research 7.
Toronto: John Libbey & Company Ltd.; 1996, pp. 281–9.
3. Perusse L, Chagnon YC, Dionne FT, Bouchard C. The
human obesity gene map: the 1996 update. Obes Res. 1997;
5:49 – 61.
4. Chagnon YC, Perusse L, Bouchard C. The human obesity
gene map: the 1997 update. Obes Res. 1998;6:76 –92.
5. Perusse L, Chagnon YC, Weisnagel J, Bouchard C. The human
obesity gene map: the 1998 update. Obes Res. 1999;7:111–29.
6. Chagnon YC, Perusse L, Weisnagel JS, Rankinen T,
Bouchard C. The human obesity gene map: the 1999 update.
Obes Res. 2000;8:89 –117.
7. Perusse L, Chagnon YC, Weisnagel SJ, et al. The human
obesity gene map: the 2000 update. Obes Res. 2001;9:135– 69.
410
OBESITY RESEARCH Vol. 12 No. 3 March 2004
8. Rankinen T, Perusse L, Weisnagel SJ, Snyder EE, Chagnon YC, Bouchard C. The human obesity gene map: the
2001 update. Obes Res. 2002;10:196 –243.
9. Chagnon YC, Rankinen T, Snyder EE, Weisnagel SJ,
Perusse L, Bouchard C. The human obesity gene map: the
2002 update. Obes Res. 2003;11:313– 67.
10. Walsh S, Anderson M, Cartinhour SW. ACEDB: a database for genome information. Methods Biochem Anal. 1998;
39:299 –318.
11. Kelley S. Getting started with Acedb. Brief Bioinform. 2000;
1:131–7.
12. Waterston R, Sulston J. The genome of Caenorhabditis
elegans. Proc Natl Acad Sci U S A. 1995;92:10836 – 40.
13. Thorisson GA, Stein LD. The SNP Consortium website:
past, present and future. Nucleic Acids Res. 2003;31:124 –7.
14. Stein LD, Thierry-Mieg J. Scriptable access to the Caenorhabditis elegans genome sequence and other ACEDB databases. Genome Res. 1998;8:1308 –15.
15. Antonarakis SE. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working
Group. Hum Mutat. 1998;11:1–3.
16. Gene Ontology Consortium. Creating the gene ontology
resource: design and implementation. Genome Res. 2001;11:
1425–33.
17. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T,
O’Rahilly S. Clinical spectrum of obesity and mutations in the
melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085–95.
18. Hebebrand J, Fichter M, Gerber G, et al. Genetic predisposition to obesity in bulimia nervosa: a mutation screen of the
melanocortin-4 receptor gene. Mol Psychiatry. 2002;7:647–51.
19. Hinney A, Hohmann S, Geller F, et al. Melanocortin-4
receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are
compatible with a major gene effect for extreme obesity.
J Clin Endocrinol Metab. 2003;88:4258 – 67.
20. Marti A, Corbalan MS, Forga L, Martinez JA, Hinney A,
Hebebrand J. A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes Relat Metab Disord. 2003;27:385– 8.
21. Tao YX, Segaloff DL. Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology. 2003;144:4544 –51.
22. Yeo GS, Lank EJ, Farooqi IS, Keogh J, Challis BG,
O’Rahilly S. Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts
receptor function through multiple molecular mechanisms.
Hum Mol Genet. 2003;12:561–74.
23. Nijenhuis WA, Garner KM, van Rozen RJ, Adan RA.
Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. J Biol Chem. 2003;
278:22939 – 45.
24. Lubrano-Berthelier C, Cavazos M, Dubern B, et al. Molecular genetics of human obesity-associated MC4R mutations. Ann N Y Acad Sci. 2003;994:49 –57.
25. Branson R, Potoczna N, Kral JG, Lentes KU, Hoehe MR,
Horber FF. Binge eating as a major phenotype of melanocortin
4 receptor gene mutations. N Engl J Med. 2003;348:1096 –103.
26. Challis BG, Pritchard LE, Creemers JW, et al. A missense mutation disrupting a dibasic prohormone processing
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet. 2002;11:1997–2004.
Savage DB, Agostini M, Barroso I, et al. Digenic inheritance of severe insulin resistance in a human pedigree. Nat
Genet. 2002;31:379 – 84.
Mantovani G, Romoli R, Weber G, et al. Mutational analysis of GNAS1 in patients with pseudohypoparathyroidism:
identification of two novel mutations. J Clin Endocrinol
Metab. 2000;85:4243– 8.
Ahrens W, Hiort O, Staedt P, Kirschner T, Marschke C,
Kruse K. Analysis of the GNAS1 gene in Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab. 2001;86:
4630 – 4.
Linglart A, Carel JC, Garabedian M, Le T, Mallet E,
Kottler ML. GNAS1 lesions in pseudohypoparathyroidism
Ia and Ic: genotype phenotype relationship and evidence of
the maternal transmission of the hormonal resistance. J Clin
Endocrinol Metab. 2002;87:189 –97.
Lim SH, Poh LK, Cowell CT, Tey BH, Loke KY. Mutational analysis of the GNAS1 exons encoding the stimulatory
G protein in five patients with pseudohypoparathyroidism
type 1a. J Pediatr Endocrinol Metab. 2002;15:259 – 68.
Rickard SJ, Wilson LC. Analysis of GNAS1 and overlapping transcripts identifies the parental origin of mutations in
patients with sporadic Albright hereditary osteodystrophy
and reveals a model system in which to observe the effects of
splicing mutations on translated and untranslated messenger
RNA. Am J Hum Genet. 2003;72:961–74.
Phelan MC, Rogers RC, Clarkson KB, et al. Albright
hereditary osteodystrophy and del(2) (q37.3) in four unrelated individuals. Am J Med Genet. 1995;58:1–7.
Wilson LC, Leverton K, Oude Luttikhuis ME, et al.
Brachydactyly and mental retardation: an Albright hereditary
osteodystrophy-like syndrome localized to 2q37. Am J Hum
Genet. 1995;56:400 –7.
Davids MS, Crawford E, Weremowicz S, et al. STK25 is
a candidate gene for pseudopseudohypoparathyroidism.
Genomics. 2001;77:2– 4.
Schmidt HH, Genschel J, Baier P, et al. Dyslipemia in
familial partial lipodystrophy caused by an R482W mutation
in the LMNA gene. J Clin Endocrinol Metab. 2001;86:
2289 –95.
Garg A, Speckman RA, Bowcock AM. Multisystem dystrophy syndrome due to novel missense mutations in the
amino-terminal head and alpha-helical rod domains of the
lamin A/C gene. Am J Med. 2002;112:549 –55.
van der Kooi AJ, Bonne G, Eymard B, et al. Lamin A/C
mutations with lipodystrophy, cardiac abnormalities, and
muscular dystrophy. Neurology. 2002;59:620 –3.
Caux F, Dubosclard E, Lascols O, et al. A new clinical
condition linked to a novel mutation in lamins A and C with
generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab. 2003;88:1006 –13.
Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T.
PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002;51:3586 –90.
41. Savage DB, Tan GD, Acerini CL, et al. Human metabolic
syndrome resulting from dominant-negative mutations in the
nuclear receptor peroxisome proliferator-activated receptorgamma. Diabetes. 2003;52:910 –7.
42. Heon E, Greenberg A, Kopp KK, et al. VSX1: a gene for
posterior polymorphous dystrophy and keratoconus. Hum
Mol Genet. 2002;11:1029 –36.
43. Wollnik B, Kayserili H, Uyguner O, Tukel T, YukselApak M. Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family. Ann Genet. 2002;
45:213–7.
44. Amor DJ. Morbid obesity and hyperphagia in the WAGR
syndrome. Clin Dysmorphol. 2002;11:73– 4.
45. Chao LY, Mishra R, Strong LC, Saunders GF. Missense
mutations in the DNA-binding region and termination codon
in PAX6. Hum Mutat. 2003;21:138 – 45.
46. Groussin L, Jullian E, Perlemoine K, et al. Mutations of
the PRKAR1A gene in Cushing’s syndrome due to sporadic
primary pigmented nodular adrenocortical disease. J Clin
Endocrinol Metab. 2002;87:4324 –9.
47. Stergiopoulos SG, Stratakis CA. Human tumors associated
with Carney complex and germline PRKAR1A mutations: a
protein kinase A disease! FEBS Lett. 2003;546:59 – 64.
48. Stratakis CA. Clinical genetics of multiple endocrine neoplasias, Carney complex and related syndromes. J Endocrinol Invest. 2001;24:370 – 83.
49. Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR,
Katsanis N. Identification of a novel Bardet-Biedl syndrome
protein, BBS7, that shares structural features with BBS1 and
BBS2. Am J Hum Genet. 2003;72:650 – 8.
50. Beales PL, Badano JL, Ross AJ, et al. Genetic interaction
of BBS1 mutations with alleles at other BBS loci can result
in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet.
2003;72:1187–99.
51. Mykytyn K, Nishimura DY, Searby CC, et al. Evaluation
of complex inheritance involving the most common BardetBiedl syndrome locus (BBS1). Am J Hum Genet. 2003;72:
429 –37.
52. Agarwal AK, Simha V, Oral EA, et al. Phenotypic and
genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 2003;88:4840 –7.
53. Kolehmainen J, Black GC, Saarinen A, et al. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in
vesicle-mediated sorting and intracellular protein transport.
Am J Hum Genet. 2003;72:1359 – 69.
54. Odievre MH, Lombes A, Dessemme P, et al. A secondary
respiratory chain defect in a patient with Fanconi-Bickel
syndrome. J Inherit Metab Dis. 2002;25:379 – 84.
55. Matsuura T, Tamura T, Chinen Y, Ohta T. A novel
mutation (N32K) of GLUT2 gene in a Japanese patient with
Fanconi-Bickel syndrome. Clin Genet. 2002;62:255– 6.
56. Baumstark A, Lower KM, Sinkus A, et al. Novel PHF6
mutation p. D333del causes Borjeson-Forssman-Lehmann
syndrome. J Med Genet. 2003;40:e50.
57. Castro NH, dos Santos RC, Nelson R, et al. Shashi XLMR
syndrome: report of a second family. Am J Med Genet.
2003;118A:49 –51.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
411
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
58. Li M, Shuman C, Fei YL, et al. GPC3 mutation analysis in
a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome. Am J Med
Genet. 2001;102:161– 8.
59. Mariani S, Iughetti L, Bertorelli R, et al. Genotype/phenotype correlations of males affected by Simpson-GolabiBehmel syndrome with GPC3 gene mutations: patient report
and review of the literature. J Pediatr Endocrinol Metab.
2003;16:225–32.
60. Fryns JP, Haspeslagh M, Dereymaeker AM, Volcke P,
Van den Berghe H. A peculiar subphenotype in the fra(X)
syndrome: extreme obesity-short stature-stubby hands and
feet-diffuse hyperpigmentation. Further evidence of disturbed hypothalamic function in the fra(X) syndrome? Clin
Genet. 1987;32:388 –92.
61. de Vries BB, Fryns JP, Butler MG, et al. Clinical and
molecular studies in fragile X patients with a Prader-Willilike phenotype. J Med Genet. 1993;30:761– 6.
62. Schrander-Stumpel C, Gerver WJ, Meyer H, Engelen J,
Mulder H, Fryns JP. Prader-Willi-like phenotype in fragile
X syndrome. Clin Genet. 1994;45:175– 80.
63. Quan F, Zonana J, Gunter K, Peterson KL, Magenis RE,
Popovich BW. An atypical case of fragile X syndrome
caused by a deletion that includes the FMR1 gene. Am J Hum
Genet. 1995;56:1042–51.
64. Phan LK, Lin F, LeDuc CA, Chung WK, Leibel RL. The
mouse mahoganoid coat color mutation disrupts a novel C3HC4
RING domain protein. J Clin Invest. 2002;110:1449 –59.
65. Miller KA, Gunn TM, Carrasquillo MM, Lamoreux ML,
Galbraith DB, Barsh GS. Genetic studies of the mouse
mutations mahogany and mahoganoid. Genetics. 1997;146:
1407–15.
66. Kero JT, Savontaus E, Mikola M, et al. Obesity in transgenic female mice with constitutively elevated luteinizing
hormone secretion. Am J Physiol Endocrinol Metab. 2003;
285:E812– 8.
67. Matsumoto T, Takeyama K, Sato T, Kato S. Androgen
receptor functions from reverse genetic models. J Steroid
Biochem Mol Biol. 2003;85:95–9.
68. Bradshaw AD, Graves DC, Motamed K, Sage EH.
SPARC-null mice exhibit increased adiposity without significant differences in overall body weight. Proc Natl Acad Sci
U S A. 2003;100:6045–50.
69. Wallenius V, Wallenius K, Ahren B, et al. Interleukin-6-deficient
mice develop mature-onset obesity. Nat Med. 2002;8:75–9.
70. Serra C, Federici M, Buongiorno A, et al. Transgenic mice
with dominant negative PKC-theta in skeletal muscle: a new
model of insulin resistance and obesity. J Cell Physiol.
2003;196:89 –97.
71. Hirosumi J, Tuncman G, Chang L, et al. A central role for
JNK in obesity and insulin resistance. Nature. 2002;420:333– 6.
72. Walz K, Caratini-Rivera S, Bi W, et al. Modeling
del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous
gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance. Mol Cell
Biol. 2003;23:3646 –55.
73. Mouse Genome Database (MGD). Mouse Genome Informatics Web Site. Bar Harbor, ME: The Jackson Laboratory.
http://www.informatics.jax.org (Accessed December 2003).
412
OBESITY RESEARCH Vol. 12 No. 3 March 2004
74. DeBry RW, Seldin MF. Human/mouse homology relationships. Genomics. 1996;33:337–51.
75. Yamada J, Kuramoto T, Serikawa T. A rat genetic linkage
map and comparative maps for mouse or human homologous
rat genes. Mamm Genome. 1994;5:63– 83.
76. Jacob HJ, Brown DM, Bunker RK, et al. A genetic linkage
map of the laboratory rat, Rattus norvegicus. Nat Genet.
1995;9:63–9.
77. Animal Genome Database (AGP). Tsukuba, Ibaraki, Japan:
Animal Genome Research Program. http://animal.dna.
affrc.go.jp/agp (Accessed December, 2003).
78. National Animal Genome Research Program. Ames,
Iowa: U.S. Livestock Genome Mapping Projects. http://www.
genome.iastate.edu (Accessed December, 2003).
79. Smith Richards BK, Belton BN, Poole AC, et al. QTL
analysis of self-selected macronutrient diet intake: fat, carbohydrate, and total kilocalories. Physiol Genomics. 2002;
11:205–17.
80. Zhang S, Gershenfeld HK. Genetic contributions to body
weight in mice: relationship of exploratory behavior to
weight. Obes Res. 2003;11:828 –38.
81. Reed DR, Li X, McDaniel AH, et al. Loci on chromosomes
2, 4, 9, and 16 for body weight, body length, and adiposity
identified in a genome scan of an F2 intercross between the
129P3/J and C57BL/6ByJ mouse strains. Mamm Genome.
2003;14:302–13.
82. Almind K, Kulkarni RN, Lannon SM, Kahn CR. Identification of interactive loci linked to insulin and leptin in mice
with genetic insulin resistance. Diabetes. 2003;52:1535– 43.
83. Harper JM, Galecki AT, Burke DT, Pinkosky SL, Miller
RA. Quantitative trait loci for insulin-like growth factor I,
leptin, thyroxine, and corticosterone in genetically heterogeneous mice. Physiol Genomics. 2003;15:44 –51.
84. Strazzullo P, Iacone R, Iacoviello L, et al. Genetic variation in the renin-angiotensin system and abdominal adiposity
in men: the Olivetti Prospective Heart Study. Ann Intern
Med. 2003;138:17–23.
85. Pereira AC, Floriano MS, Mota GF, et al. Beta2 adrenoceptor functional gene variants, obesity, and blood pressure
level interactions in the general population. Hypertension.
2003;42:685–92.
86. Arashiro R, Katsuren K, Fukuyama S, Ohta T. Effect of
Trp64Arg mutation of the beta3-adrenergic receptor gene
and C161T substitution of the peroxisome proliferator activated receptor gamma gene on obesity in Japanese children.
Pediatr Int. 2003;45:135– 41.
87. Argyropoulos G, Rankinen T, Bai F, et al. The agoutirelated protein and body fatness in humans. Int J Obes Relat
Metab Disord. 2003;27:276 – 80.
88. Yang WS, Tsou PL, Lee WJ, et al. Allele-specific differential expression of a common adiponectin gene polymorphism related to obesity. J Mol Med. 2003;81:428 –34.
89. Ukkola O, Ravussin E, Jacobson P, Sjöström L, Bouchard C. Mutations in the adiponectin gene in lean and
obese subjects from the Swedish obese subjects cohort. Metabolism. 2003;52:881– 4.
90. Ma YQ, Thomas GN, Ng MC, et al. Association of two
apolipoprotein A-I gene MspI polymorphisms with high density lipoprotein (HDL)-cholesterol levels and indices of obe-
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
sity in selected healthy Chinese subjects and in patients with
early-onset type 2 diabetes. Clin Endocrinol (Oxf). 2003;59:
442–9.
Fiegenbaum M, Hutz MH. Further evidence for the association between obesity-related traits and the apolipoprotein
A-IV gene. Int J Obes Relat Metab Disord. 2003;27:484 –90.
Ukkola O, Joanisse DR, Tremblay A, Bouchard C. Na⫹K⫹-ATPase alpha 2-gene and skeletal muscle characteristics
in response to long-term overfeeding. J Appl Physiol. 2003;
94:1870 – 4.
Shima Y, Nakanishi K, Odawara M, Kobayashi T, Ohta
H. Association of the SNP-19 genotype 22 in the calpain-10
gene with elevated body mass index and hemoglobin A1c
levels in Japanese. Clin Chim Acta. 2003;336:89 –96.
Okura T, Koda M, Ando F, Niino N, Ohta S, Shimokata
H. Association of polymorphisms in the estrogen receptor
alpha gene with body fat distribution. Int J Obes Relat Metab
Disord. 2003;27:1020 –7.
Damcott CM, Feingold E, Moffett SP, et al. Variation in
the FABP2 promoter alters transcriptional activity and is
associated with body composition and plasma lipid levels.
Hum Genet. 2003;112:610 – 6.
Kovacs P, Lehn-Stefan A, Stumvoll M, Bogardus C, Baier
LJ. Genetic variation in the human winged helix/forkhead
transcription factor gene FOXC2 in Pima Indians. Diabetes.
2003;52:1292–5.
Brand E, Wang JG, Herrmann SM, Staessen JA. An
epidemiological study of blood pressure and metabolic phenotypes in relation to the Gbeta3 C825T polymorphism.
J Hypertens. 2003;21:729 –37.
Gelernter-Yaniv L, Feng N, Sebring NG, Hochberg Z,
Yanovski JA. Associations between a polymorphism in the
11 beta hydroxysteroid dehydrogenase type I gene and body
composition. Int J Obes Relat Metab Disord. 2003;27:
983– 6.
Berthier MT, Paradis AM, Tchernof A, et al. The interleukin 6 –174G/C polymorphism is associated with indices of
obesity in men. J Hum Genet. 2003;48:14 –9.
Escobar-Morreale HF, Calvo RM, Villuendas G, Sancho
J, San Millan JL. Association of polymorphisms in the
interleukin 6 receptor complex with obesity and hyperandrogenism. Obes Res. 2003;11:987–96.
Stefan N, Kovacs P, Stumvoll M, et al. Metabolic effects of
the Gly1057Asp polymorphism in IRS-2 and interactions
with obesity. Diabetes. 2003;52:1544 –50.
St-Pierre J, Miller-Felix I, Paradis ME, et al. Visceral
obesity attenuates the effect of the hepatic lipase -514C⬎T
polymorphism on plasma HDL-cholesterol levels in FrenchCanadian men. Mol Genet Metab. 2003;78:31– 6.
Iliadou A, Lichtenstein P, Ahlberg S, et al. No linkage to
obesity in candidate regions of chromosome 2 and 10 in a
selected sample of Swedish twins. Twin Res. 2003;6:162–9.
Iwai N, Mannami T, Tomoike H, Ono K, Iwanaga Y. An
acyl-CoA synthetase gene family in chromosome 16p12 may
contribute to multiple risk factors. Hypertension. 2003;41:
1041– 6.
Wasserman L, Flatt SW, Natarajan L, et al. Correlates of
obesity in postmenopausal women with breast cancer: com-
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
parison of genetic, demographic, disease-related, life history
and dietary factors. Int J Obes Relat Metab Disord. 2004;28:
49 –56.
Hung CC, Farooqi IS, Ong K, et al. Contribution of variants in the small heterodimer partner gene to birthweight,
adiposity, and insulin levels: mutational analysis and association studies in multiple populations. Diabetes. 2003;52:
1288 –91.
Di Blasio AM, van Rossum EF, Maestrini S, et al. The
relation between two polymorphisms in the glucocorticoid
receptor gene and body mass index, blood pressure and
cholesterol in obese patients. Clin Endocrinol (Oxf). 2003;
59:68 –74.
Roussel R, Reis AF, Dubois-Laforgue D, Bellanne-Chantelot C, Timsit J, Velho G. The N363S polymorphism in the
glucocorticoid receptor gene is associated with overweight in
subjects with type 2 diabetes mellitus. Clin Endocrinol (Oxf).
2003;59:237– 41.
Bosse Y, Despres JP, Bouchard C, Perusse L, Vohl MC.
The peroxisome proliferator-activated receptor alpha L162V
mutation is associated with reduced adiposity. Obes Res.
2003;11:809 –16.
Rosmond R, Chagnon M, Bouchard C. The Pro12Ala
PPARgamma2 gene missense mutation is associated with
obesity and insulin resistance in Swedish middle-aged men.
Diabetes Metab Res Rev. 2003;19:159 – 63.
Doney A, Fischer B, Frew D, et al. Haplotype analysis of
the PPARgamma Pro12Ala and C1431T variants reveals
opposing associations with body weight. BMC Genet. 2002;
3:21.
Koumanis DJ, Christou NV, Wang XL, Gilfix BM. Pilot
study examining the frequency of several gene polymorphisms in a morbidly obese population. Obes Surg. 2002;12:
759 – 64.
Robitaille J, Despres JP, Perusse L, Vohl MC. The PPARgamma P12A polymorphism modulates the relationship between dietary fat intake and components of the metabolic
syndrome: results from the Quebec Family Study. Clin
Genet. 2003;63:109 –16.
Kao WH, Coresh J, Shuldiner AR, Boerwinkle E, Bray
MS, Brancati FL. Pro12Ala of the peroxisome proliferatoractivated receptor-gamma2 gene is associated with lower
serum insulin levels in nonobese African Americans: the
Atherosclerosis Risk in Communities Study. Diabetes. 2003;
52:1568 –72.
Epstein LH, Jaroni JL, Paluch RA, et al. Dopamine transporter genotype as a risk factor for obesity in AfricanAmerican smokers. Obes Res. 2002;10:1232– 40.
Tonooka N, Tomura H, Takahashi Y, et al. High frequency of mutations in the HNF-1alpha gene in non-obese
patients with diabetes of youth in Japanese and identification
of a case of digenic inheritance. Diabetologia. 2002;45:
1709 –12.
Rosmond R, Chagnon M, Bouchard C, Björntorp P.
Increased abdominal obesity, insulin and glucose levels in
nondiabetic subjects with a T29C polymorphism of the transforming growth factor-beta1 gene. Horm Res. 2003;
59:191– 4.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
413
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
118. Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E.
The CAG repeat polymorphism in the androgen receptor
gene modulates body fat mass and serum concentrations of
leptin and insulin in men. Diabetologia. 2003;46:31–9.
119. Roth SM, Metter EJ, Lee MR, Hurley BF, Ferrell RE.
C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women. J Appl Physiol.
2003;95:1425–30.
120. Corbalan MS, Marti A, Forga L, Martinez-Gonzalez MA,
Martinez JA. Beta(2)-adrenergic receptor mutation and abdominal obesity risk: effect modification by gender and
HDL-cholesterol. Eur J Nutr. 2002;41:114 – 8.
121. Gonzalez-Sanchez JL, Proenza AM, Martinez Larrad
MT, et al. The glutamine 27 glutamic acid polymorphism of
the beta2-adrenoceptor gene is associated with abdominal
obesity and greater risk of impaired glucose tolerance in men
but not in women: a population-based study in Spain. Clin
Endocrinol (Oxf). 2003;59:476 – 81.
122. Gustafson DR, Wen MJ, Koppanati BM. Androgen receptor gene repeats and indices of obesity in older adults. Int J
Obes Relat Metab Disord. 2003;27:75– 81.
123. Baghaei F, Rosmond R, Westberg L, et al. The CYP19
gene and associations with androgens and abdominal obesity
in premenopausal women. Obes Res. 2003;11:578 – 85.
124. Ukkola O, Chagnon M, Tremblay A, Bouchard C. Genetic variation at the adipsin locus and response to long-term
overfeeding. Eur J Clin Nutr. 2003;57:1073– 8.
125. Herrmann SM, Wang JG, Staessen JA, et al. Uncoupling
protein 1 and 3 polymorphisms are associated with waist-tohip ratio. J Mol Med. 2003;81:327–32.
126. Walston J, Andersen RE, Seibert M, et al. Arg64 beta3adrenoceptor variant and the components of energy expenditure. Obes Res. 2003;11:509 –11.
127. Kubaszek A, Pihlajamaki J, Punnonen K, Karhapaa P,
Vauhkonen I, Laakso M. The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin
sensitivity. Diabetes. 2003;52:558 – 61.
128. Stefan N, Vozarova B, Del Parigi A, et al. The Gln223Arg
polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism. Int J Obes Relat Metab Disord. 2002;26:1629 –32.
129. Muller YL, Bogardus C, Beamer BA, Shuldiner AR,
Baier LJ. A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with
predictors of obesity and type 2 diabetes in Pima Indians.
Diabetes. 2003;52:1864 –71.
130. Muller YL, Bogardus C, Pedersen O, Baier L. A
Gly482Ser missense mutation in the peroxisome proliferatoractivated receptor gamma coactivator-1 is associated with
altered lipid oxidation and early insulin secretion in Pima
Indians. Diabetes. 2003;52:895– 8.
131. Mottagui-Tabar S, Ryden M, Lofgren P, et al. Evidence
for an important role of perilipin in the regulation of human
adipocyte lipolysis. Diabetologia. 2003;46:789 –97.
132. Gonzalez-Sanchez JL, Martinez-Larrad MT, FernandezPerez C, Kubaszek A, Laakso M, Serrano-Rios M. K121Q
PC-1 gene polymorphism is not associated with insulin resistance in a Spanish population. Obes Res. 2003;11:603–5.
414
OBESITY RESEARCH Vol. 12 No. 3 March 2004
133. Schalin-Jantti C, Valli-Jaakola K, Oksanen L, et al. Melanocortin-3-receptor gene variants in morbid obesity. Int J
Obes Relat Metab Disord. 2003;27:70 – 4.
134. Suviolahti E, Ridderstrale M, Almgren P, et al. Proopiomelanocortin gene is associated with serum leptin levels
in lean but not in obese individuals. Int J Obes Relat Metab
Disord. 2003;27:1204 –11.
135. Matsushita H, Kurabayashi T, Tomita M, Kato N,
Tanaka K. Effects of uncoupling protein 1 and beta3-adrenergic receptor gene polymorphisms on body size and serum
lipid concentrations in Japanese women. Maturitas. 2003;45:
39 – 45.
136. Tremblay A, Bouchard L, Bouchard C, Despres JP,
Drapeau V, Perusse L. Long-term adiposity changes are
related to a glucocorticoid receptor polymorphism in young
females. J Clin Endocrinol Metab. 2003;88:3141–5.
137. Dishy V, Gupta S, Landau R, et al. G-protein beta3 subunit
825 C/T polymorphism is associated with weight gain during
pregnancy. Pharmacogenetics. 2003;13:241–2.
138. Hauner H, Meier M, Jockel KH, Frey UH, Siffert W.
Prediction of successful weight reduction under sibutramine
therapy through genotyping of the G-protein beta3 subunit
gene (GNB3) C825T polymorphism. Pharmacogenetics.
2003;13:453–9.
139. Peters WR, MacMurry JP, Walker J, Giese RJ Jr, Comings DE. Phenylethanolamine N-methyltransferase G-148A
genetic variant and weight loss in obese women. Obes Res.
2003;11:415–9.
140. Shiwaku K, Nogi A, Anuurad E, et al. Difficulty in losing
weight by behavioral intervention for women with Trp64Arg
polymorphism of the beta3-adrenergic receptor gene. Int J
Obes Relat Metab Disord. 2003;27:1028 –36.
141. Garenc C, Perusse L, Chagnon YC, et al. Effects of
beta2-adrenergic receptor gene variants on adiposity: the
HERITAGE Family Study. Obes Res. 2003;11:612– 8.
142. Schauble N, Geller F, Siegfried W, et al. No evidence for
involvement of the promoter polymorphism -866 G/A of the
UCP2 gene in childhood-onset obesity in humans. Exp Clin
Endocrinol Diabetes. 2003;111:73– 6.
143. Duarte NL, Colagiuri S, Palu T, Wang XL, Wilcken DE.
A 45-bp insertion/deletion polymorphism of uncoupling protein 2 in relation to obesity in Tongans. Obes Res. 2003;11:
512–7.
144. Sesti G, Cardellini M, Marini MA, et al. A common
polymorphism in the promoter of UCP2 contributes to the
variation in insulin secretion in glucose-tolerant subjects.
Diabetes. 2003;52:1280 –3.
145. Rosmond R, Bouchard C, Björntorp P. Lack of association between the uncoupling protein-2 Ala55Val gene polymorphism and phenotypic features of the Metabolic Syndrome. Biochim Biophys Acta. 2002;1588:103–5.
146. Sivenius K, Niskanen L, Laakso M, Uusitupa M. A deletion in the alpha2B-adrenergic receptor gene and autonomic
nervous function in central obesity. Obes Res. 2003;11:962–
70.
147. Suzuki N, Matsunaga T, Nagasumi K, et al. Alpha(2B)adrenergic receptor deletion polymorphism associates with
autonomic nervous system activity in young healthy Japanese. J Clin Endocrinol Metab. 2003;88:1184 –7.
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
148. Sykiotis GP, Polyzogopoulou E, Georgopoulos NA, et al.
The alpha2B adrenergic receptor deletion/insertion polymorphism in morbid obesity. Clin Auton Res. 2003;13:203–7.
149. Martinez JA, Corbalan MS, Sanchez-Villegas A, Forga
L, Marti A, Martinez-Gonzalez MA. Obesity risk is associated with carbohydrate intake in women carrying the
Gln27Glu beta2-adrenoceptor polymorphism. J Nutr. 2003;
133:2549 –54.
150. van Tilburg JH, Wijmenga C, van Bakel H, Rozeman L,
Pearson PL, van Haeften TW. Relationship of beta2-adrenergic receptor polymorphism with obesity in type 2 diabetes. Diabetes Care. 2003;26:251–2.
151. Duarte NL, Colagiuri S, Palu T, Wang XL, Wilcken DE.
Obesity, type II diabetes and the beta 2 adrenoceptor gene
Gln27Glu polymorphism in the Tongan population. Clin Sci
(Lond). 2003;104:211–5.
152. Ahluwalia M, Evans M, Morris K, et al. The influence of
the Pro12Ala mutation of the PPAR-gamma receptor gene on
metabolic and clinical characteristics in treatment-naive patients with type 2 diabetes. Diabetes Obes Metab. 2002;4:
376 – 8.
153. Bluher M, Paschke R. Analysis of the Relationship between
PPAR-gamma 2 gene variants and severe insulin resistance
in obese patients with impaired glucose tolerance. Exp Clin
Endocrinol Diabetes. 2003;111:85–90.
154. Urbanek M, Du Y, Silander K, et al. Variation in resistin
gene promoter not associated with polycystic ovary syndrome. Diabetes. 2003;52:214 –7.
155. Ochi M, Osawa H, Onuma H, et al. The absence of
evidence for major effects of the frequent SNP ⫹299G⬎A in
the resistin gene on susceptibility to insulin resistance syndrome associated with Japanese type 2 diabetes. Diabetes
Res Clin Pract. 2003;61:191– 8.
156. Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes.
2003;52:1611– 8.
157. Um JY, Mun KS, An NH, et al. Polymorphism of angiotensin-converting enzyme gene and BMI in obese Korean
women. Clin Chim Acta. 2003;328:173– 8.
158. Okumura K, Matsui H, Ogawa Y, et al. The polymorphism
of the beta3-adrenergic receptor gene is associated with
reduced low-density lipoprotein particle size. Metabolism.
2003;52:356 – 61.
159. Marques-Vidal P, Bongard V, Ruidavets JB, et al. Obesity
and alcohol modulate the effect of apolipoprotein E polymorphism on lipids and insulin. Obes Res. 2003;11:1200 – 6.
160. Guerra A, Rego C, Castro EM, Seixas S, Rocha J. Influence of apolipoprotein e polymorphism on cardiovascular
risk factors in obese children. Ann Nutr Metab. 2003;47:49 –
54.
161. Rasmussen SK, Urhammer SA, Berglund L, et al. Variants within the calpain-10 gene on chromosome 2q37
(NIDDM1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians. Diabetes. 2002;51:3561–7.
162. Malecki MT, Klupa T, Wolkow P, Bochenski J, Wanic K,
Sieradzki J. Association study of the vitamin D: 1alpha-
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
hydroxylase (CYP1alpha) gene and type 2 diabetes mellitus
in a Polish population. Diabetes Metab. 2003;29:119 –24.
Coudreau SK, Tounian P, Bonhomme G, et al. Role of the
DGAT gene C79T single-nucleotide polymorphism in
French obese subjects. Obes Res. 2003;11:1163–7.
Southon A, Walder K, Sanigorski AM, et al. The Taq IA
and Ser311 Cys polymorphisms in the dopamine D2 receptor
gene and obesity. Diabetes Nutr Metab. 2003;16:72– 6.
Treiber FA, Barbeau P, Harshfield G, et al. Endothelin-1
gene Lys198Asn polymorphism and blood pressure reactivity. Hypertension. 2003;42:494 –9.
Jin JJ, Nakura J, Wu Z, et al. Association of endothelin-1
gene variant with hypertension. Hypertension. 2003;41:
163–7.
Milewicz A, Demissie M, Zatonska K, et al. Influence of
dietary and genetic factors on metabolic status in obese and
lean postmenopausal women. Gynecol Endocrinol. 2003;17:
333– 8.
Berthier MT, Houde A, Bergeron J, Prud’homme D,
Despres JP, Vohl MC. Effect of the factor VII R353Q
missense mutation on plasma apolipoprotein B levels: impact
of visceral obesity. J Hum Genet. 2003;48:367–73.
Duarte NL, Colagiuri S, Palu T, Wang XL, Wilcken DE.
Obesity, type II diabetes and the Ala54Thr polymorphism of
fatty acid binding protein 2 in the Tongan population. Mol
Genet Metab. 2003;79:183– 8.
Masuda K, Osada H, Iitsuka Y, Seki K, Sekiya S. Positive
association of maternal G protein beta3 subunit 825T allele
with reduced head circumference at birth. Pediatr Res. 2002;
52:687–91.
Bhattacharyya S, Luan J, Challis B, et al. Association of
polymorphisms in GPR10, the gene encoding the prolactinreleasing peptide receptor with blood pressure, but not obesity, in a U.K. Caucasian population. Diabetes. 2003;52:
1296 –9.
Huang QY, Shen H, Deng HY, et al. Linkage and association of the CA repeat polymorphism of the IL6 gene,
obesity-related phenotypes, and bone mineral density (BMD)
in two independent Caucasian populations. J Hum Genet.
2003;48:430 –7.
Ortlepp JR, Metrikat J, Vesper K, et al. The interleukin-6
promoter polymorphism is associated with elevated leukocyte, lymphocyte, and monocyte counts and reduced physical
fitness in young healthy smokers. J Mol Med. 2003;81:578 –
84.
Le Fur S, Le Stunff C, Bougneres P. Increased insulin
resistance in obese children who have both 972 IRS-1 and
1057 IRS-2 polymorphisms. Diabetes. 2002;51:S304 –7.
van Rossum CT, Hoebee B, van Baak MA, Mars M, Saris
WH, Seidell JC. Genetic variation in the leptin receptor
gene, leptin, and weight gain in young Dutch adults. Obes
Res. 2003;11:377– 86.
Ma YQ, Thomas GN, Ng MC, Critchley JA, Chan JC,
Tomlinson B. The lipoprotein lipase gene HindIII polymorphism is associated with lipid levels in early-onset type 2
diabetic patients. Metabolism. 2003;52:338 – 43.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
415
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
177. Monti LD, Barlassina C, Citterio L, et al. Endothelial
nitric oxide synthase polymorphisms are associated with type
2 diabetes and the insulin resistance syndrome. Diabetes.
2003;52:1270 –5.
178. Mitchell SM, Weedon MN, Owen KR, et al. Genetic variation in the small heterodimer partner gene and young-onset
type 2 diabetes, obesity, and birth weight in U.K. subjects.
Diabetes. 2003;52:1276 –9.
179. Witchel SF, Trivedi RN, Kammerer C. Frequency of the
T228A polymorphism in the SORBS1 gene in children with
premature pubarche and in adolescent girls with hyperandrogenism. Fertil Steril. 2003;80:128 –32.
180. Pihlajamaki J, Ylinen M, Karhapaa P, Vauhkonen I,
Laakso M. The effect of the -308A allele of the TNF-alpha
gene on insulin action is dependent on obesity. Obes Res.
2003;11:912–7.
181. Adeyemo A, Luke A, Cooper R, et al. A genome-wide scan
for body mass index among Nigerian families. Obes Res.
2003;11:266 –73.
182. Gorlova O, Amos C, Wang N, Shete S, Turner S, Boerwinkle E. Genetic linkage and imprinting effects on body
mass index in children and young adults. Eur J Hum Genet.
2003;11:425–32.
183. Palmer L, Buxbaum S, Larkin E, et al. A whole-genome
scan for obstructive sleep apnea and obesity. Am J Hum
Genet. 2003;72:340 –50.
184. Platte P, Papanicolaou G, Johnston J, et al. A study of
linkage and association of body mass index in the Old Order
Amish. Am J Med Genet. 2003;121C:71– 80.
185. Luke A, Wu X, Zhu X, Kan D, Su Y, Cooper R. Linkage
for BMI at 3q27 region confirmed in an African-American
population. Diabetes. 2003;52:1284 –7.
186. Li WD, Li D, Wang S, Zhang S, Zhao H, Price RA.
Linkage and linkage disequilibrium mapping of genes influencing human obesity in chromosome region 7q22.1–7q35.
Diabetes. 2003;52:1557– 61.
187. Dong C, Wang S, Li W, Li D, Zhao H, Price R. Interacting genetic loci on chromosomes 20 and 10 influence
extreme human obesity. Am J Hum Genet. 2003;72:115–
24.
188. Saar K, Geller F, Ruschendorf F, et al. Genome scan for
childhood and adolescent obesity in German families. Pediatrics. 2003;111:321–7.
189. Comuzzie AG, Hixson JE, Almasy L, et al. A major
quantitative trait locus determining serum leptin levels and
fat mass is located on human chromosome 2. Nat Genet.
1997;15:273– 6.
190. Hager J, Dina C, Francke S, et al. A genome-wide scan for
human obesity genes reveals a major susceptibility locus on
chromosome 10. Nat Genet. 1998;20:304 – 8.
191. Kissebah A, Sonnenberg G, Myklebust J, et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes
of the metabolic syndrome. Proc Natl Acad Sci U S A.
2000;97:14478 – 83.
192. Clement K, Vaisse C, Lahlou N, et al. A mutation in the
human leptin receptor gene causes obesity and pituitary
dysfunction. Nature. 1998;392:398 – 401.
193. Krude H, Biebermann H, Luck W, Horn R, Brabant G,
Gruters A. Severe early-onset obesity, adrenal insufficiency
416
OBESITY RESEARCH Vol. 12 No. 3 March 2004
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
and red hair pigmentation caused by POMC mutations in
humans. Nat Genet. 1998;19:155–7.
Jackson RS, Creemers JWM, Ohagi S, et al. Obesity and
impaired prohormone processing associated with mutations
in the human prohormone convertase 1 gene. Nat Genet.
1997;16:303– 6.
Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset
obesity in humans. Nature. 1997;387:903– 8.
Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune
system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab. 1999;84:3686 –
95.
Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A
leptin missense mutation associated with hypogonadism and
morbid obesity. Nat Genet. 1998;18:213–5.
Dubern B, Clement K, Pelloux V, et al. Mutational analysis
of melanocortin-4 receptor, agouti-related protein, and alphamelanocyte-stimulating hormone genes in severely obese
children. J Pediatr. 2001;139:204 –9.
Farooqi IS, Yeo GS, Keogh JM, et al. Dominant and
recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 2000;106:
271–9.
Hamann A, Busing B, Munzberg H, et al. Missense variants in the human cholecystokinin type A receptor gene: no
evidence for association with early-onset obesity. Horm
Metab Res. 1999;31:287– 8.
Gu W, Tu Z, Kleyn PW, et al. Identification and functional
analysis of novel human melanocortin-4 receptor variants.
Diabetes. 1999;48:635–9.
Hinney A, Schmidt A, Nottebom K, et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly
inherited obesity in humans. J Clin Endocrinol Metab. 1999;
84:1483– 6.
Sina M, Hinney A, Ziegler A, et al. Phenotypes in three
pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor
gene. Am J Hum Genet. 1999;65:1501–7.
Jacobson P, Ukkola O, Rankinen T, et al. Melanocortin 4
receptor sequence variations are seldom a cause of human
obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort. J Clin Endocrinol Metab.
2002;87:4442– 6.
Kobayashi H, Ogawa Y, Shintani M, et al. A novel homozygous missense mutation of melanocortin-4 receptor
(MC4R) in a Japanese woman with severe obesity. Diabetes.
2002;51:243– 6.
Lubrano-Berthelier C, Durand E, Dubern B, et al. Intracellular retention is a common characteristic of childhood
obesity-associated MC4R mutations. Hum Mol Genet. 2003;
12:145–53.
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
207. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand
B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin
Invest. 2000;106:253– 62.
208. Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant
form of obesity. Nat Genet. 1998;20:113– 4.
209. Yeo GSH, Farooqi IS, Aminian S, Halsall DJ, Stanhope
RG. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20:111–2.
210. Collin GB, Marshall JD, Boerkoel CF, et al. Alstrom
syndrome: further evidence for linkage to human chromosome 2p13. Hum Genet. 1999;105:474 –9.
211. Collin GB, Marshall JD, Ikeda A, et al. Mutations in
ALMS1 cause obesity, type 2 diabetes and neurosensory
degeneration in Alstrom syndrome. Nat Genet. 2002;31:
74 – 8.
212. Hearn T, Renforth GL, Spalluto C, et al. Mutation of
ALMS1, a large gene with a tandem repeat encoding 47
amino acids, causes Alstrom syndrome. Nat Genet. 2002;31:
79 – 83.
213. Macari F, Lautier C, Girardet A, et al. Refinement of
genetic localization of the Alstrom syndrome on chromosome 2p12–13 by linkage analysis in a North African family.
Hum Genet. 1998;103:658 – 61.
214. Katsanis N, Lewis RA, Stockton DW, et al. Delineation of
the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a
small region of 11q13, through linkage and haplotype analysis of 91 pedigrees. Am J Hum Genet. 1999;65:1672–9.
215. Mykytyn K, Nishimura DY, Searby CC, et al. Identification of the gene (BBS1) most commonly involved in BardetBiedl syndrome, a complex human obesity syndrome. Nat
Genet. 2002;31:435– 8.
216. Young TL, Woods MO, Parfrey PS, Green JS, Hefferton
D, Davidson WS. A founder effect in the newfoundland
population reduces the Bardet-Biedl syndrome I (BBS1)
interval to 1 cM. Am J Hum Genet. 1999;65:1680 –7.
217. Bruford EA, Riise R, Teague PW, et al. Linkage mapping
in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21. Genomics. 1997;41:93–9.
218. Kwitek-Black AE, Carmi R, Duyk GM, et al. Linkage
of Bardet-Biedl syndrome to chromosome 16q and evidence for non-allelic genetic heterogeneity. Nat Genet.
1993;5:392– 6.
219. Nishimura DY, Searby CC, Carmi R, et al. Positional
cloning of a novel gene on chromosome 16q causing BardetBiedl syndrome (BBS2). Hum Mol Genet. 2001;10:865–74.
220. Beales PL, Katsanis N, Lewis RA, et al. Genetic and
mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the
critical intervals of other loci. Am J Hum Genet. 2001;68:
606 –16.
221. Sheffield VC, Carmi R, Kwitek-Black A, et al. Identification of a Bardet-Biedl syndrome locus on chromosome 3 and
evaluation of an efficient approach to homozygosity mapping. Hum Mol Genet. 1994;3:1331–5.
222. Young TL, Woods MO, Parfrey PS, et al. Canadian Bardet-Biedl syndrome family reduces the critical region of
BBS3 (3p) and presents with a variable phenotype. Am J Med
Genet. 1998;78:461–7.
223. Carmi R, Rokhlina T, Kwitek-Black AE, et al. Use of a
DNA pooling strategy to identify a human obesity syndrome
locus on chromosome 15. Hum Mol Genet. 1995;4:9 –13.
224. Gorman S, Haider N, Grieshammer U, et al. The cloning
and developmental expression of unconventional myosin
IXA (MYO9A) a gene in the Bardet-Biedl syndrome (BBS4)
region at chromosome 15q22– q23. Genomics. 1999;59:150 –
60.
225. Katsanis N, Eichers ER, Ansley SJ, et al. BBS4 is a minor
contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance. Am J Hum Genet. 2002;71:22–9.
226. Mykytyn K, Braun T, Carmi R, et al. Identification of the
gene that, when mutated, causes the human obesity syndrome
BBS4. Nat Genet. 2001;28:188 –91.
227. Woods M, Young T, Parfrey P, Hefferton D, Green J,
Davidson W. Genetic heterogeneity of Bardet-Biedl syndrome in a distinct Canadian population: evidence for a fifth
locus. Genomics. 1999;55:2–9.
228. Young TL, Penney L, Woods MO, et al. A fifth locus for
Bardet-Biedl syndrome maps to chromosome 2q31. Am J
Hum Genet. 1999;64:900 – 4.
229. Katsanis N, Beales PL, Woods MO, et al. Mutations in
MKKS cause obesity, retinal dystrophy and renal malformations associated with bardet-biedl syndrome. Nat Genet.
2000;26:67–70.
230. Slavotinek AM, Stone EM, Mykytyn K, et al. Mutations in
MKKS cause Bardet-Biedl syndrome. Nat Genet. 2000;26:
15– 6.
231. Slavotinek AM, Searby C, Al-Gazali L, et al. Mutation
analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients. Hum
Genet. 2002;110:561–7.
232. Agarwal AK, Arioglu E, De Almeida S, et al. AGPAT2 is
mutated in congenital generalized lipodystrophy linked to
chromosome 9q34. Nat Genet. 2002;31:21–3.
233. Garg A, Wilson R, Barnes R, et al. A gene for congenital
generalized lipodystrophy maps to human chromosome
9q34. J Clin Endocrinol Metab. 1999;84:3390 – 4.
234. Magre J, Delepine M, Khallouf E, et al. Identification of
the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001;28:365–70.
235. Heathcote K, Rajab A, Magre J, et al. Molecular analysis
of Berardinelli-Seip congenital lipodystrophy in Oman: evidence for multiple loci. Diabetes. 2002;51:1291–3.
236. Rajab A, Heathcote K, Joshi S, Jeffery S, Patton M.
Heterogeneity for congenital generalized lipodystrophy in
seventeen patients from Oman. Am J Med Genet. 2002;110:
219 –25.
237. Matthijs G, Schollen E, Pardon E, et al. Mutations in
PMMM2, a phosphomannomutase gene on chromosome
16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet. 1997;16:88 –92. [Published erratum in Nat Genet. 1997;16:316.]
OBESITY RESEARCH Vol. 12 No. 3 March 2004
417
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
238. Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet.
2001;102:125–35.
239. Tahvanainen E, Norio R, Karila E, et al. Cohen syndrome
gene assigned to the long arm of chromosome 8 by linkage
analysis. Nat Genet. 1994;7:201– 4.
240. Mendonca BB, Osorio MG, Latronico AC, Estefan V, Lo
LS, Arnhold IJ. Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone
deficiency due to deletion of A301,G302 in the PROP1 gene.
J Clin Endocrinol Metab. 1999;84:942–5.
241. Rosenbloom AL, Almonte AS, Brown MR, Fisher DA,
Baumbach L, Parks JS. Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the
PROP1 gene. J Clin Endocrinol Metab. 1999;84:50 –7.
242. Akagi M, Inui K, Nakajima S, et al. Mutation analysis of
two Japanese patients with Fanconi-Bickel syndrome. J Hum
Genet. 2000;45:60 –2.
243. Burwinkel B, Sanjad SA, Al-Sabban E, Al-Abbad A,
Kilimann MW. A mutation in GLUT2, not in phosphorylase
kinase subunits, in hepato-renal glycogenosis with Fanconi
syndrome and low phosphorylase kinase activity. Hum
Genet. 1999;105:240 –3.
244. Santer R, Schneppenheim R, Dombrowski A, Gotze H,
Steinmann B, Schaub J. Mutations in GLUT2, the gene for
the liver-type glucose transporter, in patients with FanconiBickel syndrome. Nat Genet. 1997;17:324 – 6. [Published
erratum in Nat Genet. 1998;18:298.]
245. Santer R, Groth S, Kinner M, et al. The mutation spectrum
of the facilitative glucose transporter gene SLC2A2
(GLUT2) in patients with Fanconi-Bickel syndrome. Hum
Genet. 2002;110:21–9.
246. Sakamoto O, Ogawa E, Ohura T, et al. Mutation analysis
of the GLUT2 gene in patients with Fanconi-Bickel syndrome. Pediatr Res. 2000;48:586 –9.
247. Tsuda M, Kitasawa E, Ida H, Eto Y, Owada M. A newly
recognized missense mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome. Eur J Pediatr. 2000;
159:867.
248. Salvatori R, Hayashida CY, Aguiar-Oliveira MH, et al.
Familial dwarfism due to a novel mutation of the growth
hormone-releasing hormone receptor gene. J Clin Endocrinol Metab. 1999;84:917–23.
249. Wajnrajch MP, Gertner JM, Harbison MD, Chua SC,
Leibel RL. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet. 1996;12:88 –90.
250. Bellus GA, Hefferon TW, Ortiz de Luna RI et al. Achondroplasia is defined by recurrent G380R mutations of
FGFR3. Am J Hum Genet. 1995;56:368 –73.
251. Rousseau F, Bonaventure J, Legeai-Mallet L, et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994;371:252– 4.
252. Shiang R, Thompson LM, Zhu YZ, et al. Mutations in the
transmembrane domain of FGFR3 cause the most common
genetic form of dwarfism, achondroplasia. Cell. 1994;78:
335– 42.
253. Superti-Furga A, Eich G, Bucher HU, et al. A glycine
375-to-cysteine substitution in the transmembrane domain of
418
OBESITY RESEARCH Vol. 12 No. 3 March 2004
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
the fibroblast growth factor receptor-3 in a newborn with
achondroplasia. Eur J Pediatr. 1995;154:215–9.
Ahmed SF, Dixon PH, Bonthron DT, et al. GNAS1 mutational analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf). 1998;49:525–31.
Aldred MA, Trembath RC. Activating and inactivating
mutations in the human GNAS1 gene. Hum Mutat. 2000;16:
183–9.
Farfel Z, Iiri T, Shapira H, Roitman A, Mouallem M,
Bourne HR. Pseudohypoparathyroidism, a novel mutation
in the beta gamma-contact region of Gs alpha impairs receptor stimulation. J Biol Chem. 1996;271:19653–5.
Fischer JA, Egert F, Werder E, Born W. An inherited
mutation associated with functional deficiency of the alphasubunit of the guanine nucleotide-binding protein Gs in pseudo- and pseudopseudohypoparathyroidism. J Clin Endocrinol Metab. 1998;83:935– 8.
Iiri T, Herzmark P, Nakamoto JM, van Dop C, Bourne
HR. Rapid GDP release from Gs alpha in patients with gain
and loss of endocrine function. Nature. 1994;371:164 – 8.
Ishikawa Y, Tajima T, Nakae J, et al. Two mutations of the
Gsalpha gene in two Japanese patients with sporadic
pseudohypoparathyroidism type Ia. J Hum Genet. 2001;46:
426 –30.
Patten JL, Johns DR, Valle D, et al. Mutation in the gene
encoding the stimulatory G protein of adenylate cyclase in
Albright’s hereditary osteodystrophy. N Engl J Med. 1990;
322:1412–9.
Schwindinger WF, Miric A, Zimmerman D, Levine MA.
A novel Gs alpha mutant in a patient with Albright hereditary
osteodystrophy uncouples cell surface receptors from adenylyl cyclase. J Biol Chem. 1994;269:25387–91.
Warner DR, Gejman PV, Collins RM, Weinstein LS. A
novel mutation adjacent to the switch III domain of G(S
alpha) in a patient with pseudohypoparathyroidism. Mol Endocrinol. 1997;11:1718 –27.
Warner DR, Weng G, Yu S, Matalon R, Weinstein LS. A
novel mutation in the switch 3 region of Gsalpha in a patient
with Albright hereditary osteodystrophy impairs GDP binding and receptor activation. J Biol Chem. 1998;273:23976 –
83.
Weinstein LS, Gejman PV, Friedman E, et al. Mutations
of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis.
Proc Natl Acad Sci U S A. 1990;87:8287–90.
Weinstein LS, Gejman PV, de Mazancourt P, American
N, Spiegel AM. A heterozygous 4-bp deletion mutation in
the Gs alpha gene (GNAS1) in a patient with Albright
hereditary osteodystrophy. Genomics. 1992;13:1319 –21.
Wilson LC, Oude Luttikhuis ME, Clayton PT, Fraser
WD, Trembath RC. Parental origin of Gs alpha gene mutations in Albright’s hereditary osteodystrophy. J Med Genet.
1994;31:835–9.
Yu D, Yu S, Schuster V, Kruse K, Clericuzio C, Weinstein L. Identification of two novel deletion mutations within
the G(s)alpha gene (GNAS1) in albright hereditary osteodystrophy. J Clin Endocrinol Metab. 1999;84:3254 –9.
Hedeland H, Berntorp K, Arheden K, Kristoffersson U.
Pseudohypoparathyroidism type I and Albright’s hereditary
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
269.
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
osteodystrophy with a proximal 15q chromosomal deletion
in mother and daughter. Clin Genet. 1992;42:129 –34.
Gillessen-Kaesbach G, Demuth S, Thiele H, Theile U,
Lich C, Horsthemke B. A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by
an imprinting defect. Eur J Hum Genet. 1999;7:638 – 44.
Stratakis CA, Lafferty A, Taymans SE, Gafni RI, Meck
JM, Blancato J. Anisomastia associated with interstitial
duplication of chromosome 16, mental retardation, obesity,
dysmorphic facies, and digital anomalies: molecular mapping of a new syndrome by fluorescent in situ hybridization
and microsatellites to 16q13 (D16S419 –D16S503). J Clin
Endocrinol Metab. 2000;85:3396 – 401.
Anderson J, Khan M, David W, et al. Confirmation of
linkage of hereditary partial lipodystrophy to chromosome
1q21–22. Am J Med Genet. 1999;82:161–5.
Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in
canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000;9:109 –12.
Garg A, Vinaitheerthan M, Weatherall PT, Bowcock
AM. Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of
missense mutations in lamin a/c gene. J Clin Endocrinol
Metab. 2001;86:59 – 65.
Peters J, Barnes R, Bennett L, Gitomer W, Bowcock A,
Garg A. Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21–22. Nat
Genet. 1998;18:292–5.
Shackleton S, Lloyd DJ, Jackson SN, et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat
Genet. 2000;24:153– 6.
Speckman RA, Garg A, Du F, et al. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations
in the globular C-terminal domain of lamin A/C. Am J Hum
Genet. 2000;66:1192– 8.
Agarwal AK, Garg A. A novel heterozygous mutation in
peroxisome proliferator-activated receptor-gamma gene in a
patient with familial partial lipodystrophy. J Clin Endocrinol
Metab. 2002;87:408 –11.
Cama A, de la Luz Sierra M, Ottini L, et al. A mutation in
the tyrosine kinase domain of the insulin receptor associated
with insulin resistance in an obese woman. J Clin Endocrinol
Metab. 1991;73:894 –901.
Globerman H, Karnieli E. Analysis of the insulin receptor
gene tyrosine kinase domain in obese patients with hyperandrogenism, insulin resistance and acanthosis nigricans (type
C insulin resistance). Int J Obes Relat Metab Disord. 1998;
22:349 –53.
Kim H, Kadowaki H, Sakura H, et al. Detection of mutations in the insulin receptor gene in patients with insulin
resistance by analysis of single-stranded conformational
polymorphisms. Diabetologia. 1992;35:261– 6.
Krook A, Kumar S, Laing I, Boulton AJ, Wass JA,
O’Rahilly S. Molecular scanning of the insulin receptor gene
in syndromes of insulin resistance. Diabetes. 1994;43:357–
68.
282. Moller DE, Cohen O, Yamaguchi Y, et al. Prevalence of
mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance. Diabetes.
1994;43:247–55.
283. Shimada F, Taira M, Suzuki Y, et al. Insulin-resistant
diabetes associated with partial deletion of insulin- receptor
gene. Lancet. 1990;335:1179 – 81.
284. Shimada F, Suzuki Y, Taira M, et al. Abnormal messenger
ribonucleic acid (mRNA) transcribed from a mutant insulin
receptor gene in a patient with type A insulin resistance.
Diabetologia. 1992;35:639 – 44.
285. Wertheimer E, Litvin Y, Ebstein RP, et al. Deletion of
exon 3 of the insulin receptor gene in a kindred with a
familial form of insulin resistance. J Clin Endocrinol Metab.
1994;78:1153– 8.
286. Biswas S, Munier FL, Yardley J, et al. Missense mutations
in COL8A2, the gene encoding the alpha2 chain of type VIII
collagen, cause two forms of corneal endothelial dystrophy.
Hum Mol Genet. 2001;10:2415–23.
287. Heon E, Mathers WD, Alward WL, et al. Linkage of
posterior polymorphous corneal dystrophy to 20q11. Hum
Mol Genet. 1995;4:485– 8.
288. Boccaccio I, Glatt-Deeley H, Watrin F, Roeckel N, Lalande M, Muscatelli F. The human MAGEL2 gene and its
mouse homologue are paternally expressed and mapped to
the Prader-Willi region. Hum Mol Genet. 1999;8:2497–505.
289. de los Santos T, Schweizer J, Rees CA, Francke U. Small
evolutionarily conserved RNA, resembling C/D box small
nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which is
highly expressed in brain. Am J Hum Genet. 2000;67:1067–
82.
290. Gallagher RC, Pils B, Albalwi M, Francke U. Evidence for
the role of PWCR1/HBII-85 C/D box small nucleolar RNAs
in Prader-Willi syndrome. Am J Hum Genet. 2002;71:669 –
78.
291. Gilhuis HJ, van Ravenswaaij CM, Hamel BJ, Gabreels
FJ. Interstitial 6q deletion with a Prader-Willi-like phenotype: a new case and review of the literature. Eur J Paediatr
Neurol. 2000;4:39 – 43.
292. Hordijk R, Wierenga H, Scheffer H, Leegte B, Hofstra
RM, Stolte-Dijkstra I. Maternal uniparental disomy for
chromosome 14 in a boy with a normal karyotype. J Med
Genet. 1999;36:782–5.
293. Jay P, Rougeulle C, Massacrier A, et al. The human necdin
gene NDN, is maternally imprinted and located in the PraderWilli syndrome chromosomal region. Nat Genet. 1997;17:
357– 61.
294. Jong MT, Gray TA, Ji Y, et al. A novel imprinted gene,
encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region.
Hum Mol Genet. 1999;8:783–93.
295. Kuslich CD, Kobori JA, Mohapatra G, Gregorio-King C,
Donlon TA. Prader-Willi syndrome is caused by disruption
of the SNRPN gene. Am J Hum Genet. 1999;64:70 – 6.
296. Lee S, Kozlov S, Hernandez L, et al. Expression and
imprinting of MAGEL2 suggest a role in Prader-Willi syndrome and the homologous murine imprinting phenotype.
Hum Mol Genet. 2000;9:1813–9.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
419
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
297. Meguro M, Mitsuya K, Nomura N, et al. Large-scale
evaluation of imprinting status in the Prader-Willi syndrome
region: an imprinted direct repeat cluster resembling small
nucleolar RNA genes. Hum Mol Genet. 2001;10:383–94.
298. Ming JE, Blagowidow N, Knoll JH, et al. Submicroscopic
deletion in cousins with Prader-Willi syndrome causes a
grandmatrilineal inheritance pattern: effects of imprinting.
Am J Med Genet. 2000;92:19 –24.
299. Ohta T, Gray TA, Rogan PK, et al. Imprinting-mutation
mechanisms in Prader-Willi syndrome. Am J Hum Genet.
1999;64:397– 413.
300. Robinson WP, Bottani A, Xie YG, et al. Molecular, cytogenetic, and clinical investigations of Prader-Willi syndrome
patients. Am J Hum Genet. 1991;49:1219 –34.
301. Stein CK, Stred SE, Thomson LL, Smith FC, Hoo JJ.
Interstitial 6q deletion and Prader-Willi-like phenotype. Clin
Genet. 1996;49:306 –10.
302. Turleau C, Demay G, Cabanis MO, Lenoir G, de
Grouchy J. 6q1 monosomy: a distinctive syndrome. Clin
Genet. 1988;34:38 – 42.
303. Wevrick R, Kerns JA, Francke U. Identification of a novel
paternally expressed gene in the Prader-Willi syndrome region. Hum Mol Genet. 1994;3:1877– 82.
304. Wirth J, Back E, Huttenhofer A, et al. A translocation
breakpoint cluster disrupts the newly defined 3⬘ end of the
SNURF-SNRPN transcription unit on chromosome 15. Hum
Mol Genet. 2001;10:201–10.
305. Villa A, Urioste M, Bofarull JM, Martinez-Frias ML. De
novo interstitial deletion q16.2q21 on chromosome 6. Am J
Med Genet. 1995;55:379 – 83.
306. Holder JL Jr, Butte NF, Zinn AR. Profound obesity associated with a balanced translocation that disrupts the SIM1
gene. Hum Mol Genet. 2000;9:101– 8.
307. Roland B, Lowry RB, Cox DM, Ferreira P, Lin CC.
Familial complex chromosomal rearrangement resulting in
duplication/deletion of 6q14 to 6q16. Clin Genet. 1993;43:
117–21.
308. Smith A. The diagnosis of Prader-Willi syndrome. J Paediatr Child Health. 1999;35:335–7.
309. Faivre L, Cormier-Daire V, Lapierre JM, et al. Deletion
of the SIM1 gene (6q16.2) in a patient with a Prader-Willilike phenotype. J Med Genet. 2002;39:594 – 6.
310. Bamshad M, Lin RC, Law DJ, et al. Mutations in human
TBX3 alter limb, apocrine and genital development in ulnarmammary syndrome. Nat Genet. 1997;16:311–5.
311. Behr M, Ramsden DB, Loos U. Deoxyribonucleic acid
binding and transcriptional silencing by a truncated
c-erbAB1 thyroid hormone receptor identified in a severely
retarded patient with resistance to thyroid hormone. J Clin
Endocrinol Metab. 1997;82:1081–7.
312. Bamshad M, Le T, Watkins WS, et al. The spectrum of
mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome. Am J Hum Genet. 1999;64:1550 –
62.
313. Gul D, Ogur G, Tunca Y, Ozcan O. Third case of
WAGR syndrome with severe obesity and constitutional
deletion of chromosome (11)(p12p14). Am J Med Genet.
2002;107:70 –1.
420
OBESITY RESEARCH Vol. 12 No. 3 March 2004
314. Marlin S, Couet D, Lacombe D, Cessans C, Bonneau D.
Obesity: a new feature of WAGR (del 11p) syndrome. Clin
Dysmorphol. 1994;3:255–7.
315. Tiberio G, Digilio MC, Giannotti A. Obesity and WAGR
syndrome. Clin Dysmorphol. 2000;9:63– 4.
316. Gecz J, Baker E, Donnelly A, et al. Fibroblast growth factor
homologous factor 2 (FHF2): gene structure, expression and
mapping to the Borjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a
BFLS-like patient. Hum Genet. 1999;104:56 – 63.
317. Kubota T, Oga S, Ohashi H, Iwamoto Y, Fukushima Y.
Borjeson-Forssman-Lehmann syndrome in a woman with
skewed X-chromosome inactivation. Am J Med Genet. 1999;
87:258 – 61.
318. Lower KM, Turner G, Kerr BA, et al. Mutations in PHF6
are associated with Borjeson-Forssman-Lehmann syndrome.
Nat Genet. 2002;32:661–5.
319. Merry DE, Lesko JG, Sosnoski DM, et al. Choroideremia
and deafness with stapes fixation: a contiguous gene deletion
syndrome in Xq21. Am J Hum Genet. 1989;45:530 – 40.
320. Schwartz M, Yang HM, Niebuhr E, Rosenberg T, Page
DC. Regional localization of polymorphic DNA loci on the
proximal long arm of the X chromosome using deletions
associated with choroideremia. Hum Genet. 1988;78:156 –
60.
321. Leshinsky-Silver E, Zinger A, Bibi CN, et al. MEHMO
(Mental retardation, Epileptic seizures, Hypogenitalism, Microcephaly, Obesity): a new X-linked mitochondrial disorder. Eur J Hum Genet. 2002;10:226 –30.
322. Steinmuller R, Steinberger D, Muller U. MEHMO (mental
retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment
of disease locus to Xp21.1-p22.13. Eur J Hum Genet. 1998;
6:201– 6.
323. DeLozier-Blanchet CD, Haenggeli CA, Bottani A.
MEHMO, a novel syndrome: assignment of disease locus to
Xp21.1-p22.13. Mental retardation, epileptic seizures, hypogonadism and genitalism, microcephaly, obesity. Eur J Hum
Genet. 1999;7:621–2.
324. Ahmad W, De Fusco M, ul Haque MF, et al. Linkage
mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity. Eur J Hum Genet.
1999;7:828 –32.
325. Shashi V, Berry MN, Shoaf S, Sciote JJ, Goldstein D,
Hart TC. A unique form of mental retardation with a distinctive phenotype maps to Xq26 – q27. Am J Hum Genet.
2000;66:469 –79. [Published erratum in Am J Hum Genet.
2000;66:1472.]
326. Monaghan KG, Van Dyke DL, Feldman GL. Prader-Willilike syndrome in a patient with an Xq23q25 duplication.
Am J Med Genet. 1998;80:227–31.
327. Hughes-Benzie RM, Pilia G, Xuan JY, et al. SimpsonGolabi-Behmel syndrome: genotype/phenotype analysis of
18 affected males from 7 unrelated families. Am J Med
Genet. 1996;66:227–34.
328. Lindsay S, Ireland M, O’Brien O et al. Large scale deletions in the GPC3 gene may account for a minority of cases
of Simpson-Golabi-Behmel syndrome. J Med Genet. 1997;
34:480 –3.
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
329. Neri G, Gurrieri F, Zanni G, Lin A. Clinical and molecular
aspects of the Simpson-Golabi-Behmel syndrome. Am J Med
Genet. 1998;79:279 – 83.
330. Okamoto N, Yagi M, Imura K, Wada Y. A clinical and
molecular study of a patient with Simpson-Golabi-Behmel
syndrome. J Hum Genet. 1999;44:327–9.
331. Veugelers M, Vermeesch J, Watanabe K, Yamaguchi Y,
Marynen P, David G. GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene
cluster in one family with Simpson-Golabi-Behmel syndrome. Genomics. 1998;53:1–11.
332. Veugelers M, Cat BD, Muyldermans SY, et al. Mutational
analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in
patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. Hum
Mol Genet. 2000;9:1321– 8.
333. Xuan JY, Hughes-Benzie RM, MacKenzie AE. A small
interstitial deletion in the GPC3 gene causes Simpson-Golabi-Behmel syndrome in a Dutch-Canadian family. J Med
Genet. 1999;36:57– 8.
334. Brzustowicz LM, Farrell S, Khan MB, Weksberg R. Mapping of a new SGBS locus to chromosome Xp22 in a family
with a severe form of Simpson-Golabi-Behmel syndrome.
Am J Hum Genet. 1999;65:779 – 83.
335. Gedeon A, Mulley J, Turner G. Gene localisation for
Wilson-Turner syndrome (WTS:MIM 309585). Am J Med
Genet. 1996;64:80 –1.
336. Wilson M, Mulley J, Gedeon A, Robinson H, Turner G.
New X-linked syndrome of mental retardation, gynecomastia, and obesity is linked to DXS255. Am J Med Genet.
1991;40:406 –13.
337. Chen H, Charlat O, Tartaglia LA, et al. Evidence that the
diabetes gene encodes the leptin receptor: identification of a
mutation in the leptin receptor gene in db/db mice. Cell.
1996;84:491–5.
338. Tartaglia LA, Dembski M, Weng X, et al. Identification
and expression cloning of a leptin receptor, OB-R. Cell.
1995;83:1263–71.
339. Peterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld
mouse results from mutation of a new gene encoding a
nuclear protein, lipin. Nat Genet. 2001;27:121– 4.
340. Naggert JK, Fricker LD, Varlamov O, et al. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.
Nat Genet. 1995;10:135– 42.
341. Fumakoshi A, Shinozaki H, Masada M, et al. An animal
model of congenital defect of gene expression of cholecystokinin (CCK)-A receptor. Biochem Biophys Res Commun.
1993;210:787–96.
342. Schwartz GJ, Whitney A, Skoglund C, Castonguay TW,
Moran TH. Decreased responsiveness to dietary fat in Otsuka Long-Evans Tokushima fatty rats lacking CCK-A receptors. Am J Physiol. 1999;277:R1144 –51.
343. Donahue LR, Beamer WG. Growth hormone deficiency in
‘little’ mice results in aberrant body composition, reduced
insulin-like growth factor-I and insulin-like growth factorbinding protein-3 (IGFBP-3), but does not affect IGFBP-2,
-1 or -4. J Endocrinol. 1993;136:91–104.
344. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L,
Friedman JM. Positional cloning of the mouse obese gene
and its human homologue. Nature. 1994;372:425–32.
345. Kapeller R, Moriarty A, Strauss A, et al. Tyrosine phosphorylation of tub and its association with Src homology 2
domain-containing proteins implicate tub in intracellular signaling by insulin. J Biol Chem. 1999;274:24980 – 6.
346. Kleyn PW, Fan W, Kovats SG, et al. Identification and
characterization of the mouse obesity gene tubby: a member
of a novel gene family. Cell. 1996;85:281–90.
347. Noben-Trauth K, Naggert JK, North MA, Nishina PM. A
candidate gene for the mouse mutation tubby. Nature. 1996;
380:534 – 8.
348. Nagle DL, McGrail SH, Vitale J, et al. The mahogany
protein is a receptor involved in suppression of obesity.
Nature. 1999;398:148 –52.
349. Gunn TM, Miller KA, He L, et al. The mouse mahogany
locus encodes a transmembrane form of human attractin.
Nature. 1999;398:152– 6.
350. Wilson BD, Ollmann MM, Kang L, Stoffel M, Bell GI,
Barsh GS. Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet. 1995;4:
223–30.
351. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil
SJ. Continuous fatty acid oxidation and reduced fat storage
in mice lacking acetyl-CoA carboxylase 2. Science. 2001;
291:2613– 6.
352. Jong MC, Voshol PJ, Muurling M, et al. Protection from
obesity and insulin resistance in mice overexpressing human
apolipoprotein C1. Diabetes. 2001;50:2779 – 85.
353. Moitra J, Mason MM, Olive M, et al. Life without white
fat: a transgenic mouse. Genes Dev. 1998;12:3168 – 81.
354. Ohki-Hamazaki H, Watase K, Yamamoto K, et al. Mice
lacking bombesin receptor subtype-3 develop metabolic defects and obesity. Nature. 1997;390:165–9.
355. Murray I, Havel PJ, Sniderman AD, Cianflone K. Reduced body weight, adipose tissue, and leptin levels despite
increased energy intake in female mice lacking acylationstimulating protein. Endocrinology. 2000;141:1041–9.
356. Wang ND, Finegold MJ, Bradley A, et al. Impaired energy
homeostasis in C/EBP alpha knockout mice. Science. 1995;
269:1108 –12.
357. Tanaka T, Yoshida N, Kishimoto T, Akira S. Defective
adipocyte differentiation in mice lacking the C/EBPbeta
and/or C/EBPdelta gene. Embo J. 1997;16:7432– 43.
358. Yamada M, Miyakawa T, Duttaroy A, et al. Mice lacking
the M3 muscarinic acetylcholine receptor are hypophagic
and lean. Nature. 2001;410:207–12.
359. Jones ME, Thorburn AW, Britt KL, et al. Aromatasedeficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A. 2000;97:12735– 40.
360. Kozak LP, Kozak UC, Clarke GT. Abnormal brown and
white fat development in transgenic mice overexpressing
glycerol 3-phosphate dehydrogenase. Genes Dev. 1991;5:
2256 – 64.
361. Zhou QY, Palmiter RD. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell. 1995;83:1197–
209.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
421
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
362. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from
insulin resistance through a targeted mutation in aP2, the
adipocyte fatty acid binding protein. Science. 1996;
274:1377–9.
363. Smith SJ, Cases S, Jensen DR, et al. Obesity resistance and
multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet. 2000;25:87–90.
364. Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR. Estrogen deficiency, obesity, and skeletal abnormalities in follicle- stimulating hormone receptor
knockout (FORKO) female mice. Endocrinology. 2000;141:
4295–308.
365. Ma YH, Hu JH, Zhou XG, et al. Transgenic mice overexpressing gamma-aminobutyric acid transporter subtype I develop obesity. Cell Res. 2000;10:303–10.
366. Tsukiyama-Kohara K, Poulin F, Kohara M, et al. Adipose tissue reduction in mice lacking the translational inhibitor 4E- BP1. Nat Med. 2001;7:1128 –32.
367. Cai A, Hyde JF. The human growth hormone-releasing
hormone transgenic mouse as a model of modest obesity:
differential changes in leptin receptor (OBR) gene expression
in the anterior pituitary and hypothalamus after fasting and
OBR localization in somatotrophs. Endocrinology. 1999;
140:3609 –14.
368. Marsh DJ, Weingarth DT, Novi DE, et al. Melaninconcentrating hormone 1 receptor-deficient mice are
lean, hyperactive, and hyperphagic and have altered
metabolism. Proc Natl Acad Sci U S A. 2002;99:
3240 –5.
369. Masaki T, Yoshimatsu H, Chiba S, Watanabe T, Sakata
T. Targeted disruption of histamine H1-receptor attenuates
regulatory effects of leptin on feeding, adiposity, and UCP
family in mice. Diabetes. 2001;50:385–91.
370. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation
of orexin neurons in mice results in narcolepsy, hypophagia,
and obesity. Neuron. 2001;30:345–54.
371. Fain JN, Del Mar NA, Meade CA, Reiner A, Goldowitz
D. Abnormalities in the functioning of adipocytes from R6/2
mice that are transgenic for the Huntington’s disease mutation. Hum Mol Genet. 2001;10:145–52.
372. Anand A, Chada K. In vivo modulation of Hmgic reduces
obesity. Nat Genet. 2000;24:377– 80.
373. Masuzaki H, Paterson J, Shinyama H, et al. A transgenic
model of visceral obesity and the metabolic syndrome. Science. 2001;294:2166 –70.
374. Dong ZM, Gutierrez-Ramos JC, Coxon A, Mayadas TN,
Wagner DD. A new class of obesity genes encodes leukocyte adhesion receptors. Proc Natl Acad Sci U S A. 1997;94:
7526 –30.
375. Hirsch E, Irikura VM, Paul SM, Hirsh D. Functions of
interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci U S A. 1996;93:11008 –
13.
376. Beattie JH, Wood AM, Newman AM, et al. Obesity and
hyperleptinemia in metallothionein (-I and -II) null mice.
Proc Natl Acad Sci U S A. 1998;95:358 – 63.
422
OBESITY RESEARCH Vol. 12 No. 3 March 2004
377. Good DJ, Porter FD, Mahon KA, Parlow AF, Westphal
H, Kirsch IR. Hypogonadism and obesity in mice with a
targeted deletion of the Nhlh2 gene. Nat Genet. 1997;15:
397– 401.
378. Cummings DE, Brandon EP, Planas JV, Motamed K,
Idzerda RL, McKnight GS. Genetically lean mice result
from targeted disruption of the RII beta subunit of protein
kinase A. Nature. 1996;382:622– 6.
379. Martinez-Botas J, Anderson JB, Tessier D, et al. Absence
of perilipin results in leanness and reverses obesity in
Lepr(db/db) mice. Nat Genet. 2000;26:474 –9.
380. Tansey JT, Sztalryd C, Gruia-Gray J, et al. Perilipin
ablation results in a lean mouse with aberrant adipocyte
lipolysis, enhanced leptin production, and resistance to dietinduced obesity. Proc Natl Acad Sci U S A. 2001;98:6494 –9.
381. Ludwig DS, Tritos NA, Mastaitis JW, et al. Melaninconcentrating hormone overexpression in transgenic mice
leads to obesity and insulin resistance. J Clin Invest. 2001;
107:379 – 86.
382. Shimada M, Tritos NA, Lowell BB, Flier JS, MaratosFlier E. Mice lacking melanin-concentrating hormone are
hypophagic and lean. Nature. 1998;396:670 – 4.
383. Ueno N, Inui A, Iwamoto M, et al. Decreased food intake
and body weight in pancreatic polypeptide-overexpressing
mice. Gastroenterology. 1999;117:1427–32.
384. Elchebly M, Payette P, Michaliszyn E, et al. Increased
insulin sensitivity and obesity resistance in mice lacking the
protein tyrosine phosphatase-1B gene. Science. 1999;283:
1544 – 8.
385. Reizes O, Lincecum J, Wang Z, et al. Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell. 2001;106:105–16.
386. Shimano H, Horton JD, Hammer RE, Shimomura I,
Brown MS, Goldstein JL. Overproduction of cholesterol
and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest.
1996;98:1575– 84.
387. Shimomura I, Hammer RE, Richardson JA, et al. Insulin
resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 1998;12:3182–
94.
388. Udy GB, Towers RP, Snell RG, et al. Requirement of
STAT5b for sexual dimorphism of body growth rates and
liver gene expression. Proc Natl Acad Sci U S A. 1997;94:
7239 – 44.
389. Clouthier DE, Comerford SA, Hammer RE. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. J Clin Invest.
1997;100:2697–713.
390. Hahm S, Mizuno TM, Wu TJ, et al. Targeted deletion of
the Vgf gene indicates that the encoded secretory peptide
precursor plays a novel role in the regulation of energy
balance. Neuron. 1999;23:537– 48.
391. Dragani TA, Zeng ZB, Canzian F, et al. Mapping of body
weight loci on mouse chromosome X. Mamm Genome. 1995;
6:778 – 81.
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
392. Taylor BA, Phillips SJ. Detection of obesity QTLs on
mouse chromosomes 1 and 7 by selective DNA pooling.
Genomics. 1996;34:389 –98.
393. Taylor BA, Phillips SJ. Obesity QTLs on mouse chromosome 2 and 17. Genomics. 1997;43:249 –57.
394. West DB, Goudey-Lefevre J, York B, Truett GE. Dietary
obesity linked to genetic loci on chromosomes 9 and 15 in a
polygenic mouse model. J Clin Invest. 1994;94:1410 – 6.
395. West DB, Waguespack J, York B, Goudey-Lebevre J,
Price RA. Genetics of dietary obesity in AKR/J x SWR/J
mice: segregation of the trait and identification of a linked
locus on chromosome 4. Mamm Genome. 1994;5:546 –52.
396. Mehrabian M, Wen P, Fisler J, Davis R, Lusis A. Genetic
loci controlling body fat, lipoprotein metabolism, and insulin
levels in a multifactorial mouse model. J Clin Invest. 1998;
101:2485–96.
397. Pomp D. Genetic dissection of obesity in polygenic animal
models. Behav Genet. 1997;27:285–306.
398. Corva PM, Horvat S, Medrano JF. Quantitative trait loci
affecting growth in high growth (hg) mice. Mamm Genome.
2001;12:284 –90.
399. Keightley PD, Hardge T, May L, Bulfield G. A genetic
map of quantitative trait loci for body weight in the mouse.
Genetics. 1996;142:227–35.
400. Keightley PD, Morris KH, Ishikawa A, Falconer VM,
Oliver F. Test of candidate gene-quantitative trait locus
association applied to fatness in mice. Heredity. 1998;81:
630 –7.
401. Brockmann G, Timtchenko D, Das P, et al. Detection of
QTL for body weight and body fat content in mice using
genetic markers. J Anim Breed Genet. 1996;113:373–9.
402. Brockmann GA, Haley CS, Renne U, Knott SA, Schwerin
M. Quantitative trait loci affecting body weight and fatness
from a mouse line selected for extreme high growth. Genetics. 1998;150:369 – 81.
403. Brockmann GA, Kratzsch J, Haley CS, Renne U,
Schwerin M, Karle S. Single QTL effects, epistasis, and
pleiotropy account for two-thirds of the phenotypic F(2)
variance of growth and obesity in DU6i x DBA/2 mice.
Genome Res. 2000;10:1941–57.
404. Horvat S, Bunger L, Falconer V, et al. Mapping of obesity
QTLs in a cross between mouse lines divergently selected on
fat content. Mamm Genome. 2000;11:2–7.
405. Suto J, Matsuura S, Imamura K, Yamanaka H, Sekikawa
K. Genetics of obesity in KK mouse and effects of A(y)
allele on quantitative regulation. Mamm Genome. 1998;9:
506 –10.
406. Taylor BA, Tarantino LM, Phillips SJ. Gender-influenced
obesity QTLs identified in a cross involving the KK type II
diabetes-prone mouse strain. Mamm Genome. 1999;10:
963– 8.
407. Moody DE, Pomp D, Nielsen MK, Van Vleck LD. Identification of quantitative trait loci influencing traits related to
energy balance in selection and inbred lines of mice. Genetics. 1999;152:699 –711.
408. Warden CH, Fisler JS, Shoemaker SM, et al. Identification of four chromosomal loci determining obesity in a
multifactorial mouse model. J Clin Invest. 1995;95:1545–52.
409. Ueda H, Ikegami H, Kawaguchi Y, et al. Genetic analysis
of late-onset type 2 diabetes in a mouse model of human
complex trait. Diabetes. 1999;48:1168 –74.
410. Lembertas AV, Perusse L, Chagnon YC, et al. Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the
human homologous region 20q. J Clin Invest. 1997;100:
1240 –7.
411. Kluge R, Giesen K, Bahrenberg G, Plum L, Ortlepp JR,
Joost HG. Quantitative trait loci for obesity and insulin
resistance (Nob1, Nob2) and their interaction with the leptin
receptor allele (LeprA720T/T1044I) in New Zealand obese
mice. Diabetologia. 2000;43:1565–72.
412. Taylor BA, Wnek C, Schroeder D, Phillips SJ. Multiple
obesity QTLs identified in an intercross between the NZO
(New Zealand obese) and the SM (small) mouse strains.
Mamm Genome. 2001;12:95–103.
413. Reifsnyder PC, Churchill G, Leiter EH. Maternal environment and genotype interact to establish diabesity in mice.
Genome Res. 2000;10:1568 –78.
414. Collins AC, Martin ICA, Kirkpatrick BW. Growth quantitative trait loci (QTL) on mouse chromosome 10 in a
Quackenbush-Swiss x C57BL/6J backcross. Mamm Genome.
1993;4:454 – 8.
415. Anunciado RV, Nishimura M, Mori M, et al. Quantitative
trait loci for body weight in the intercross between SM/J and
A/J mice. Exp Anim. 2001;50:319 –24.
416. Cheverud JM, Routman EJ, Duarte FA, van Swinderen
B, Cothran K, Perel C. Quantitative trait loci for murine
growth. Genetics. 1996;142:1305–19.
417. Cheverud JM, Vaughn TT, Pletscher LS, et al. Genetic
architecture of adiposity in the cross of LG/J and SM/J inbred
mice. Mamm Genome. 2001;12:3–12.
418. Vaughn TT, Pletscher LS, Peripato A, et al. Mapping
quantitative trait loci for murine growth: a closer look at
genetic architecture. Genet Res. 1999;74:313–22.
419. Hirayama I, Yi Z, Izumi S, et al. Genetic analysis of obese
diabetes in the TSOD mouse. Diabetes. 1999;48:1183–91.
420. Ishikawa A, Matsuda Y, Namikawa T. Detection of quantitative trait loci for body weight at 10 weeks from Philippine
wild mice. Mamm Genome. 2000;11:824 –30.
421. Watanabe T, Okuno S, Oga K, et al. Genetic dissection of
“OLETF,” a rat model for non-insulin-dependent diabetes
mellitus: quantitative trait locus analysis of (OLETF x BN) x
OLETF. Genomics. 1999;58:233–9.
422. Kato N, Hyne G, Bihoreau MT, Gauguier D, Lathrop
GM, Rapp JP. Complete genome searches for quantitative
trait loci controlling blood pressure and related traits in four
segregating populations derived from Dahl hypertensive rats.
Mamm Genome. 1999;10:259 – 65.
423. Gauguier D, Froguel P, Parent V, et al. Chromosomal
mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet. 1996;12:38 – 43.
424. Galli J, Li LS, Glaser A, et al. Genetic analysis of noninsulin dependent diabetes mellitus in the GK rat. Nat Genet.
1996;12:31–7.
425. Chung WK, Zheng M, Chua M, et al. Genetic modifiers of
Leprfa associated with variability in insulin production and
susceptibility to NIDDM. Genomics. 1997;41:332– 44.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
423
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
426. Kanemoto N, Hishigaki H, Miyakita A, et al. Genetic
dissection of “OLETF”, a rat model for non-insulin-dependent diabetes mellitus. Mamm Genome. 1998;9:419 –25.
427. Ogino T, Wei S, Wei K, et al. Genetic evidence for obesity
loci involved in the regulation of body fat distribution in
obese type 2 diabetes rat, OLETF. Genomics. 2000;70:19 –
25.
428. Tanomura H, Miyake T, Taniguchi Y, et al. Detection of
a quantitative trait locus for intramuscular fat accumulation
using the OLETF rat. J Vet Med Sci. 2002;64:45–50.
429. Kovacs P, Kloting I. Mapping of quantitative trait loci for
body weight on chromosomes 1 and 4 in the rat. Biochem
Mol Biol Int. 1998;44:399 – 405.
430. Kloting I, Kovacs P, van den Brandt J. Quantitative trait
loci for body weight, blood pressure, blood glucose, and
serum lipids: linkage analysis with wild rats (Rattus norvegicus). Biochem Biophys Res Commun. 2001;284:1126 –33.
431. Kloting I, Kovacs P, van den Brandt J. Sex-specific and
sex-independent quantitative trait loci for facets of the metabolic syndrome in WOKW rats. Biochem Biophys Res Commun. 2001;284:150 – 6.
432. Malek M, Dekkers JC, Lee HK, et al. A molecular genome
scan analysis to identify chromosomal regions influencing
economic traits in the pig. II. Meat and muscle composition.
Mamm Genome. 2001;12:637– 45.
433. Anderson L, Haley CS, Ellegren H, et al. Genetic mapping
of quantitative trait loci for growth and fatness in pigs.
Science. 1994;263:1771– 4.
434. Knott SA, Marklund L, Haley CS, et al. Multiple marker
mapping of quantitative trait loci in a cross between outbred
wild boar and large white pigs. Genetics. 1998;149:1069 –
80.
435. Marklund L, Nystrom PE, Stern S, Andersson-Eklund L,
Andersson L. Confirmed quantitative trait loci for fatness
and growth on pig chromosome 4. Heredity. 1999;82:134 –
41.
436. Perez-Enciso M, Clop A, Noguera JL, et al. A QTL on pig
chromosome 4 affects fatty acid metabolism: evidence from
an Iberian by Landrace intercross. J Anim Sci. 2000;78:
2525–31.
437. Rattink AP, de Koning DJ, Faivre M, Harlizius B, van
Arendonk JA, Groenen MA. Fine mapping and imprinting
analysis for fatness trait QTLs in pigs. Mamm Genome.
2000;11:656 – 61.
438. de Koning DJ, Janss LL, Rattink AP, et al. Detection of
quantitative trait loci for backfat thickness and intramuscular
fat content in pigs (Sus scrofa). Genetics. 1999;152:1679 –
90.
439. Rothschild MF, Liu HC, Tuggle CK, Yu TP, Wang L.
Analysis of pig chromosome 7 genetic markers for growth
and carcass performance traits. J Anim Breed Genet. 1995;
112:341– 8.
440. Wang L, Yu TP, Tuggle CK, Liu HC, Rothschild MF. A
directed search for quantitative trait loci on chromosomes 4
and 7 in pigs. J Anim Sci. 1998;76:2560 –7.
441. de Koning DJ, Rattink AP, Harlizius B, van Arendonk
JA, Brascamp EW, Groenen MA. Genome-wide scan for
body composition in pigs reveals important role of imprinting. Proc Natl Acad Sci U S A. 2000;97:7947–50.
424
OBESITY RESEARCH Vol. 12 No. 3 March 2004
442. Harlizius B, Rattink A, Faivre M, et al. The X chromosome harbors quantitative trait loci for backfat thickness and
intramuscular fat content in pigs. Mamm Genome. 2000;11:
800 –2.
443. Wada Y, Akita T, Awata T, et al. Quantitative trait loci
(QTL) analysis in a Meishan x Gottingen cross population.
Anim Genet. 2000;31:376 – 84.
444. Walling GA, Archibald AL, Cattermole JA, et al. Mapping of quantitative trait loci on porcine chromosome 4.
Anim Genet. 1998;29:415–24.
445. Bidanel JP, Milan D, Iannuccelli N, et al. Detection of
quantitative trait loci for growth and fatness in pigs. Genet
Sel Evol. 2001;33:289 –309.
446. Rohrer GA. Identification of quantitative trait loci affecting
birth characters and accumulation of backfat and weight in a
Meishan-White composite resource population. J Anim Sci.
2000;78:2547–53.
447. Rohrer GA, Keele JW. Identification of quantitative trait
loci affecting carcass composition in swine. I. Fat deposition
traits. J Anim Sci. 1998;76:2247–54.
448. Jeon JT, Carlborg O, Tornsten A, et al. A paternally
expressed QTL affecting skeletal and cardiac muscle mass in
pigs maps to the IGF2 locus. Nat Genet. 1999;21:157– 8.
449. Nezer C, Moreau L, Brouwers B, et al. An imprinted QTL
with major effect on muscle mass and fat deposition maps to
the IGF2 locus in pigs. Nat Genet. 1999;21:155– 6.
450. MacNeil MD, Grosz MD. Genome-wide scans for QTL
affecting carcass traits in Hereford x composite double backcross populations. J Anim Sci. 2002;80:2316 –24.
451. York B, Lei K, West DB. Sensitivity to dietary obesity
linked to a locus on chromosome 15 in a CAST/Ei x
C57B1/6J F2 intercross. Mamm Genome. 1996;7:677– 81.
452. Jacob HJ, Brown DM, Bunker RK, et al. A genetic linkage
map of the laboratory rat, Rattus norvegicus. Nat Genet.
1995;9:63–9.
453. Hani EH, Clement K, Velho G, et al. Genetic studies of the
sulfonylurea receptor gene locus in NIDDM and in morbid
obesity among French Caucasians. Diabetes. 1997;46:688 –
94.
454. Lucarini N, Finocchi G, Gloria-Bottini F, et al. A possible
genetic component of obesity in childhood. Observations on
acid phosphatase polymorphism. Experientia. 1990;46:90 –1.
455. Lucarini N, Antonacci E, Bottini N, Gloria-Bottini F.
Low-molecular-weight acid phosphatase (ACP1), obesity,
and blood lipid levels in subjects with non-insulin-dependent
diabetes mellitus. Hum Biol. 1997;69:509 –15.
456. Bottini E, Gloria-Bottini F. Adenosine deaminase and body
mass index in non-insulin-dependent diabetes mellitus. Metabolism. 1999;48:949 –51.
457. Garenc C, Perusse L, Chagnon YC, et al. The alpha
2-adrenergic receptor gene and body fat content and distribution: the HERITAGE Family Study. Mol Med. 2002;8:88 –
94.
458. Oppert JM, Tourville J, Chagnon M, et al. DNA polymorphisms in alpha 2- and beta 2-adrenoceptor genes and
regional fat distribution in humans: association and linkage
studies. Obes Res. 1995;3:249 –55.
459. Heinonen P, Koulu M, Pesonen U, et al. Identification of a
three-amino acid deletion in the alpha2B-adrenergic receptor
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
460.
461.
462.
463.
464.
465.
466.
467.
468.
469.
470.
471.
472.
473.
that is associated with reduced basal metabolic rate in obese
subjects. J Clin Endocrinol Metab. 1999;84:2429 –33.
Sivenius K, Lindi V, Niskanen L, Laakso M, Uusitupa M.
Effect of a three-amino acid deletion in the alpha2B-adrenergic receptor gene on long-term body weight change in
Finnish non-diabetic and type 2 diabetic subjects. Int J Obes
Relat Metab Disord. 2001;25:1609 –14.
Dionne IJ, Garant MJ, Nolan AA, et al. Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women. Int J
Obes Relat Metab Disord. 2002;26:633–9.
Corbalan MS, Marti A, Forga L, Martinez-Gonzalez MA,
Martinez JA. The risk of obesity and the Trp64Arg polymorphism of the beta(3)-adrenergic receptor: effect modification by age. Ann Nutr Metab. 2002;46:152– 8.
Ehrenborg E, Skogsberg J, Ruotolo G, et al. The Q/E27
polymorphism in the beta2-adrenoceptor gene is associated
with increased body weight and dyslipoproteinaemia involving triglyceride-rich lipoproteins. J Intern Med. 2000;247:
651– 6.
Ellsworth DL, Coady SA, Chen W, et al. Influence of the
beta2-adrenergic receptor Arg16Gly polymorphism on longitudinal changes in obesity from childhood through young
adulthood in a biracial cohort: the Bogalusa Heart Study. Int
J Obes Relat Metab Disord. 2002;26:928 –37.
Hoffstedt J, Iliadou A, Pedersen NL, Schalling M, Arner
P. The effect of the beta(2) adrenoceptor gene Thr164Ile
polymorphism on human adipose tissue lipolytic function.
Br J Pharmacol. 2001;133:708 –12.
Ishiyama-Shigemoto S, Yamada K, Yuan X, Ichikawa F,
Nonaka K. Association of polymorphisms in the beta 2-adrenergic receptor gene with obesity, hypertriglyceridaemia,
and diabetes mellitus. Diabetologia. 1999;42:98 –101.
Large V, Hellstrom L, Reynisdottir S, et al. Human beta-2
adrenoceptor gene polymorphisms are highly frequent in
obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest. 1997;100:3005–13.
Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. Impact
of polymorphisms of the human beta2-adrenoceptor gene on
obesity in a French population. Int J Obes Relat Metab
Disord. 2000;24:382–7.
Meirhaeghe A, Luan J, Selberg-Franks P, et al. The effect
of the Gly16Arg polymorphism of the beta(2)-adrenergic
receptor gene on plasma free fatty acid levels is modulated
by physical activity. J Clin Endocrinol Metab. 2001;86:
5881–7.
Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. Beta2adrenoceptor gene polymorphism, body weight, and physical
activity. Lancet. 1999;353:896.
Moore GE, Shuldiner AR, Zmuda JM, Ferrell RE, McCole SD, Hagberg JM. Obesity gene variant and elite endurance performance. Metabolism. 2001;50:1391–2.
Mori Y, Kim-Motoyama H, Ito Y, et al. The Gln27Glu
beta2-adrenergic receptor variant is associated with obesity
due to subcutaneous fat accumulation in Japanese men. Biochem Biophys Res Commun. 1999;258:138 – 40.
Rosmond R, Ukkola O, Chagnon M, Bouchard C, Björntorp P. Polymorphisms of the beta2-adrenergic receptor
474.
475.
476.
477.
478.
479.
480.
481.
482.
483.
484.
485.
486.
gene (ADRB2) in relation to cardiovascular risk factors in
men. J Intern Med. 2000;248:239 – 44.
Ukkola O, Rankinen T, Weisnagel SJ, et al. Interactions
among the alpha2-, beta2-, and beta3-adrenergic receptor
genes and obesity-related phenotypes in the Quebec Family
Study. Metabolism. 2000;49:1063–70.
Ukkola O, Tremblay A, Bouchard C. Beta-2 adrenergic
receptor variants are associated with subcutaneous fat accumulation in response to long-term overfeeding. Int J Obes
Relat Metab Disord. 2001;25:1604 – 8.
van Rossum CT, Hoebee B, Seidell JC, et al. Genetic
factors as predictors of weight gain in young adult Dutch
men and women. Int J Obes Relat Metab Disord. 2002;26:
517–28.
Yamada K, Ishiyama-Shigemoto S, Ichikawa F, et al.
Polymorphism in the 5⬘-leader cistron of the beta2-adrenergic receptor gene associated with obesity and type 2 diabetes.
J Clin Endocrinol Metab. 1999;84:1754 –7.
Clement K, Vaisse C, Manning BSJ, et al. Genetic variation in the B3-adrenergic receptor and an increased capacity
to gain weight in patients with morbid obesity. N Engl J Med.
1995;333:352– 4.
Corella D, Guillen M, Portoles O, et al. Gender specific
associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population: interaction with a common lipoprotein
lipase gene variation. J Intern Med. 2001;250:348 – 60.
Endo K, Yanagi H, Hirano C, Hamaguchi H, Tsuchiya S,
Tomura S. Association of Trp64Arg polymorphism of the
beta3-adrenergic receptor gene and no association of
Gln223Arg polymorphism of the leptin receptor gene in
Japanese schoolchildren with obesity. Int J Obes Relat Metab
Disord. 2000;24:443–9.
Festa A, Krugluger W, Shnawa N, Hopmeier P, Haffner
SM, Schernthaner G. Trp64Arg polymorphism of the beta3-adrenergic receptor gene in pregnancy: association with
mild gestational diabetes mellitus. J Clin Endocrinol Metab.
1999;84:1695–9.
Fujisawa T, Ikegami H, Yamato E, et al. Association of
Trp64Arg mutation of the beta 3-adrenergic-receptor with
NIDDM and body weight gain. Diabetologia. 1996;39:349 –
52.
Higashi K, Ishikawa T, Ito T, Yonemura A, Shige H,
Nakamura H. Association of a genetic variation in the beta
3-adrenergic receptor gene with coronary heart disease
among Japanese. Biochem Biophys Res Commun. 1997;232:
728 –30.
Hoffstedt J, Poirier O, Thorne A, et al. Polymorphism of
the human beta(3)-adrenoceptor gene forms a well-conserved
haplotype that is associated with moderate obesity and altered receptor function. Diabetes. 1999;48:203–5.
Jeyasingam C, Bryson J, Caterson I, Yue D, Donnelly R.
Expression of the beta3-adrenoceptor gene polymorphism
(Trp64Arg) in obese diabetic and non-diabetic subjects. Clin
Exp Pharmacol Physiol. 1997;24:733–5.
Kadowaki H, Yasuda K, Iwamoto K, et al. A mutation in
the beta 3-adrenergic receptor gene is associated with obesity
and hyperinsulinemia in Japanese subjects. Biochem Biophys
Res Commun. 1995;215:555– 60.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
425
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
487. Kim-Motoyama H, Yasuda K, Yamaguchi T, et al. A
mutation of the beta 3-adrenergic receptor is associated with
visceral obesity but decreased serum triglyceride. Diabetologia. 1997;40:469 –72.
488. Marti A, Corbalan MS, Martinez-Gonzalez MA, Martinez JA. TRP64ARG polymorphism of the beta3-adrenergic
receptor gene and obesity risk: effect modification by a
sedentary lifestyle. Diabetes Obes Metab. 2002;4:428 –30.
489. McFarlane-Anderson N, Bennett F, Wilks R, et al. The
Trp64Arg mutation of the beta(3)-adrenergic receptor is associated with hyperglycemia and current body mass index in
Jamaican women. Metabolism. 1998;47:617–21.
490. Mitchell B, Blangero J, Comuzzie A, et al. A paired sibling
analysis of the beta-3 adrenergic receptor and obesity in
Mexican Americans. J Clin Invest. 1998;101:584 –7.
491. Nagase T, Aoki A, Yamamoto M, et al. Lack of association
between the Trp64 Arg mutation in the beta 3-adrenergic
receptor gene and obesity in Japanese men: a longitudinal
analysis. J Clin Endocrinol Metab. 1997;82:1284 –7.
492. Oizumi T, Daimon M, Saitoh T, et al. Genotype Arg/Arg,
but not Trp/Arg, of the Trp64Arg polymorphism of the
beta(3)-adrenergic receptor is associated with type 2 diabetes
and obesity in a large Japanese sample. Diabetes Care.
2001;24:1579 – 83.
493. Oksanen L, Mustajoki P, Kaprio J, et al. Polymorphism of
the beta 3-adrenergic receptor gene in morbid obesity. Int J
Obes Relat Metab Disord. 1996;20:1055– 61.
494. Ongphiphadhanakul B, Rajatanavin R, Chanprasertyothin S, et al. Relation of beta3-adrenergic receptor gene
mutation to total body fat but not percent body fat and insulin
levels in Thais. Metabolism. 1999;48:564 –7.
495. Sakane N, Yoshida T, Umekawa T, Kondo M, Sakai Y,
Takahashi T. Beta 3-adrenergic-receptor polymorphism: a
genetic marker for visceral fat obesity and the insulin resistance syndrome. Diabetologia. 1997;40:200 – 4.
496. Shima Y, Tsukada T, Nakanishi K, Ohta H. Association
of the Trp64Arg mutation of the beta(3)-adrenergic receptor
with fatty liver and mild glucose intolerance in Japanese
subjects. Clin Chim Acta. 1998;274:167–76.
497. Strazzullo P, Iacone R, Siani A, et al. Relationship of the
Trp64Arg polymorphism of the beta3-adrenoceptor gene to
central adiposity and high blood pressure: interaction with
age. Cross-sectional and longitudinal findings of the Olivetti
Prospective Heart Study. J Hypertens. 2001;19:399 – 406.
498. Thomas GN, Tomlinson B, Chan JC, Young RP, Critchley JA. The Trp64Arg polymorphism of the beta3-adrenergic
receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab
Disord. 2000;24:545–51.
499. Urhammer SA, Clausen JO, Hansen T, Pedersen O. Insulin sensitivity and body weight changes in young white
carriers of the codon 64 amino acid polymorphism of the beta
3-adrenergic receptor gene. Diabetes. 1996;45:1115–20.
500. Widen E, Lehto M, Kannine T, Walston J, Shuldiner AR,
Groop LC. Association of a polymorphism in the beta
3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med. 1995;333:348 –51.
501. Xinli W, Xiaomei T, Meihua P, Song L. Association of a
mutation in the beta3-adrenergic receptor gene with obesity
426
OBESITY RESEARCH Vol. 12 No. 3 March 2004
502.
503.
504.
505.
506.
507.
508.
509.
510.
511.
512.
513.
514.
515.
and response to dietary intervention in Chinese children.
Acta Paediatr. 2001;90:1233–7.
Argyropoulos G, Rankinen T, Neufeld DR, et al. A polymorphism in the human agouti-related protein is associated
with late-onset obesity. J Clin Endocrinol Metab. 2002;87:
4198 –202.
Chaves FJ, Giner V, Corella D, et al. Body weight changes
and the A-6G polymorphism of the angiotensinogen gene. Int
J Obes Relat Metab Disord. 2002;26:1173– 8.
Hegele RA, Brunt JH, Connelly PW. Genetic variation on
chromosome 1 associated with variation in body fat distribution in men. Circulation. 1995;92:1089 –93.
Rankinen T, Gagnon J, Perusse L, et al. Body fat, resting
and exercise blood pressure and the angiotensinogen M235T
polymorphism: the HERITAGE family study. Obes Res.
1999;7:423–30.
Menzaghi C, Ercolino T, Di Paola R, et al. A haplotype at
the adiponectin locus is associated with obesity and other
features of the insulin resistance syndrome. Diabetes. 2002;
51:2306 –12.
Stumvoll M, Tschritter O, Fritsche A, et al. Association of
the T-G polymorphism in adiponectin (exon 2) with obesity
and insulin sensitivity: interaction with family history of type
2 diabetes. Diabetes. 2002;51:37– 41.
Ukkola O, Ravussin E, Jacobson P, Sjöström L, Bouchard C. Mutations in the adiponectin gene in lean and
obese subjects from the Swedish obese subjects cohort. Metabolism. 2003;52:881– 4.
van’t Hooft FM, Ruotolo G, Boquist S, de Faire U, Eggertsen G, Hamsten A. Human evidence that the apolipoprotein a-II gene is implicated in visceral fat accumulation and
metabolism of triglyceride-rich lipoproteins. Circulation.
2001;104:1223– 8.
Fisher RM, Burke H, Nicaud V, Ehnholm C, Humphries
SE. Effect of variation in the apo A-IV gene on body mass
index and fasting and postprandial lipids in the European
Atherosclerosis Research Study II. J Lipid Res. 1999;40:
287–94.
Lefevre M, Lovejoy JC, DeFelice SM, et al. Common
apolipoprotein A-IV variants are associated with differences
in body mass index levels and percentage body fat. Int J
Obes Relat Metab Disord. 2000;24:945–53.
Pouliot MC, Despres JP, Dionne FT, et al. Apo B-100 gene
EcoR1 polymorphism. Relations to plasma lipoprotein
changes associated with abdominal visceral obesity. Arterioscler Thromb. 1994;14:527–33.
Rajput-Williams J, Wallis SC, Yarnell J, et al. Variation
of apolipoprotein-B gene is associated with obesity, high
blood cholesterol levels, and increased risk of coronary heart
disease. Lancet. 1988;2:1442– 6.
Saha N, Tay JSH, Heng CK, Humphries SE. DNA polymorphisms of the apolipoprotein B gene are associated with
obesity and serum lipids in healthy Indians in Singapore.
Clin Genet. 1993;44:113–20.
Vijayaraghavan S, Hitman GA, Kopelman PG. Apolipoprotein D polymorphism: a genetic marker of obesity and
hyperinsulinemia. J Clin Endocrinol Metab. 1994;79:568 –
70.
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
516. Oh JY, Barrett-Connor E. Apolipoprotein E polymorphism
and lipid levels differ by gender and family history of diabetes: the Rancho Bernardo Study. Clin Genet. 2001;60:
132–7.
517. Deriaz O, Dionne F, Perusse L, et al. DNA variation in the
genes of the Na,K-Adenosine triphosphatase and the its
relation with resting metabolic rate, respiratory quotient, and
body fat. J Clin Invest. 1994;93:838 – 43.
518. Katzmarzyk PT, Rankinen T, Perusse L, et al. Linkage
and association of the sodium potassium-adenosine triphosphatase alpha2 and beta1 genes with respiratory quotient and
resting metabolic rate in the Quebec Family Study. J Clin
Endocrinol Metab. 1999;84:2093–7.
519. Hoffstedt J, Naslund E, Arner P. Calpain-10 gene polymorphism is associated with reduced beta(3)-adrenoceptor
function in human fat cells. J Clin Endocrinol Metab. 2002;
87:3362–7.
520. Challis BG, Yeo GS, Farooqi IS, et al. The CART gene and
human obesity: mutational analysis and population genetics.
Diabetes. 2000;49:872–5.
521. Yamada K, Yuan X, Otabe S, Koyanagi A, Koyama W,
Makita Z. Sequencing of the putative promoter region of the
cocaine- and amphetamine-regulated-transcript gene and
identification of polymorphic sites associated with obesity.
Int J Obes Relat Metab Disord. 2002;26:132– 6.
522. Wolford J, Bogardus C, Prochazka M. Polymorphism in
the 3⬘ untranslated region of MTG8 is associated with obesity in Pima Indian males. Biochem Biophys Res Commun.
1998;246:624 – 6.
523. Funakoshi A, Miyasaka K, Matsumoto H, et al. Gene
structure of human cholecystokinin (CCK) type-A receptor:
body fat content is related to CCK type-A receptor gene
promoter polymorphism. FEBS Lett. 2000;466:264 – 6.
524. Han Z, Heath SC, Shmulewitz D, et al. Candidate genes
involved in cardiovascular risk factors by a family-based
association study on the island of Kosrae, Federated States of
Micronesia. Am J Med Genet. 2002;110:234 – 42.
525. Comings DE, Flanagan SD, Dietz G, Muhleman D, Knell
E, Gysin R. The dopamine D2 receptor (DRD2) as a major
gene in obesity and height. Biochem Med Metab Biol. 1993;
50:176 – 85.
526. Spitz MR, Detry MA, Pillow P, et al. Variant alleles of the
D2 dopamine receptor gene and obesity. Nutr Res. 2000;20:
371– 80.
527. Tataranni PA, Baier L, Jenkinson C, Harper I, Del Parigi
A, Bogardus C. A Ser311Cys mutation in the human dopamine receptor D2 gene is associated with reduced energy
expenditure. Diabetes. 2001;50:901– 4.
528. Thomas GN, Tomlinson B, Critchley JA. Modulation
of blood pressure and obesity with the dopamine D2
receptor gene TaqI polymorphism. Hypertension. 2000;
36:177– 82.
529. Thomas GN, Critchley JA, Tomlinson B, Cockram CS,
Chan JC. Relationships between the taqI polymorphism of
the dopamine D2 receptor and blood pressure in hyperglycaemic and normoglycaemic Chinese subjects. Clin Endocrinol (Oxf). 2001;55:605–11.
530. Deng HW, Li J, Li JL, et al. Association of estrogen
receptor-alpha genotypes with body mass index in normal
healthy postmenopausal Caucasian women. J Clin Endocrinol Metab. 2000;85:2748 –51.
531. Speer G, Cseh K, Winkler G, et al. Vitamin D and estrogen
receptor gene polymorphisms in type 2 diabetes mellitus and
in android type obesity. Eur J Endocrinol. 2001;144:385–9.
532. Hegele RA, Harris SB, Hanley AJG, Sadikian S, Connelly
PW, Zinman B. Genetic variation of intestinal fatty acid
binding protein associated with variation in body mass in
Aboriginal Canadians. J Clin Endocrinol Metab. 1996;81:
4334 –7.
533. Yamada K, Yuan X, Ishiyama S, et al. Association between Ala54Thr substitution of the fatty acid-binding protein
2 gene with insulin resistance and intra-abdominal fat thickness in Japanese men. Diabetologia. 1997;40:706 –10.
534. Siani A, Iacone R, Russo O, et al. Gly40Ser polymorphism
of the glucagon receptor gene is associated with central
adiposity in men. Obes Res. 2001;9:722– 6.
535. Hattersley AT, Beards F, Ballantyne E, Appleton M,
Harvey R, Ellard S. Mutations in the glucokinase gene of
the fetus result in reduced birth weight. Nat Genet. 1998;19:
268 –70.
536. Korbonits M, Gueorguiev M, O’Grady E, et al. A variation in the ghrelin gene increases weight and decreases
insulin secretion in tall, obese children. J Clin Endocrinol
Metab. 2002;87:4005– 8.
537. Ukkola O, Ravussin E, Jacobson P, et al. Mutations in the
preproghrelin/ghrelin gene associated with obesity in humans. J Clin Endocrinol Metab. 2001;86:3996 –9.
538. Gutersohn A, Naber C, Muller N, Erbel R, Siffert W. G
protein beta3 subunit 825 TT genotype and post-pregnancy
weight retention. Lancet. 2000;355:1240 –1.
539. Hauner H, Rohrig K, Siffert W. Effects of the G-Protein
beta3 subunit 825T allele on adipogenesis and lipolysis in
cultured human preadipocytes and adipocytes. Horm Metab
Res. 2002;34:475– 80.
540. Hegele RA, Anderson C, Young TK, Connelly PW. Gprotein beta3 subunit gene splice variant and body fat distribution in nunavut inuit. Genome Res. 1999;9:972–7.
541. Hocher B, Slowinski T, Stolze T, Pleschka A, Neumayer
HH, Halle H. Association of maternal G protein beta3 subunit 825T allele with low birthweight. Lancet. 2000;355:
1241–2.
542. Poch E, Giner V, Gonzalez-Nunez D, Coll E, Oriola J, de
la Sierra A. Association of the G protein beta3 subunit T
allele with insulin resistance in essential hypertension. Clin
Exp Hypertens. 2002;24:345–53.
543. Rankinen T, Rice T, Leon AS, et al. G protein beta 3
polymorphism and hemodynamic and body composition
phenotypes in the HERITAGE Family Study. Physiol
Genomics. 2002;8:151–7.
544. Ryden M, Faulds G, Hoffstedt J, Wennlund A, Arner P.
Effect of the (C825T) Gbeta(3) polymorphism on adrenoceptor-mediated lipolysis in human fat cells. Diabetes. 2002;51:
1601– 8.
545. Siffert W, Naber C, Walla M, Ritz E. G protein beta 3
subunit 825T allele and its potential association with obesity
in hypertensive individuals. J Hypertens. 1999;17:1095– 8.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
427
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
546. Siffert W, Forster P, Jockel K, et al. Worldwide ethnic
distribution of the G protein beta 3 subunit 825T allele and its
association with obesity in Caucasian, Chinese, and Black
African individuals. J Am Soc Nephrol. 1999;10:1921–30.
547. Orho-Melander M, Almgren P, Kanninen T, Forsblom C,
Groop L. A paired-sibling analysis of the Xbal polymorphism in the muscle glycogen synthase gene. Diabetologia.
1999;42:1138 – 45.
548. Vohl MC, Dionne F, Perusse L, Deriaz O, Chagnon M,
Bouchard C. Relation between Bg1II polymorphism in 3␤hydroxysteroid dehydrogenase gene and adipose tissue distribution in humans. Obes Res. 1994;2:444 –9.
549. Chouchane L, Danguir J, Beji C, et al. Genetic variation in
the stress protein hsp70 –2 gene is highly associated with
obesity. Int J Obes Relat Metab Disord. 2001;25:462– 6.
550. Levitan RD, Kaplan AS, Masellis M, et al. Polymorphism
of the serotonin 5-HT1B receptor gene (HTR1B) associated
with minimum lifetime body mass index in women with
bulimia nervosa. Biol Psychiatry. 2001;50:640 –3.
551. Aubert R, Betoulle D, Herbeth B, Siest G, Fumeron F.
5-HT2A receptor gene polymorphism is associated with food
and alcohol intake in obese people. Int J Obes Relat Metab
Disord. 2000;24:920 – 4.
552. Rosmond R, Bouchard C, Björntorp P. 5-HT(2A) receptor
gene promoter polymorphism in relation to abdominal obesity and cortisol. Obes Res. 2002;10:585–9.
553. Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor
gene polymorphism. Lancet. 2002;359:2086 –7.
554. Westberg L, Bah J, Rastam M, et al. Association between
a polymorphism of the 5-HT2C receptor and weight loss in
teenage girls. Neuropsychopharmacology. 2002;26:789 –93.
555. Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W,
Nonaka K. Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their
association with obesity and type II diabetes. Diabetologia.
2000;43:373– 6.
556. Sun G, Gagnon J, Chagnon Y, et al. Association and
linkage between an insulin-like growth factor-1 gene polymorphism and fat free mass in the HERITAGE family study.
Int J Obes Relat Metab Disord. 1999;23:929 –35.
557. O’Dell SD, Miller GJ, Cooper JA, et al. Apa1 polymorphism in insulin-like growth factor II (IGF2) gene and weight
in middle-aged males. Int J Obes Relat Metab Disord. 1997;
21:822–5.
558. Roth SM, Schrager MA, Metter EJ, et al. IGF2 genotype
and obesity in men and women across the adult age span. Int
J Obes Relat Metab Disord. 2002;26:585–7.
559. Dunger DB, Ong KKL, Huxtable SJ, et al. Association of
the INS VNTR with size at birth. Nat Genet. 1998;19:98 –
100.
560. Gu D, O’Dell SD, Chen XH, Miller GJ, Day IN. Evidence
of multiple causal sites affecting weight in the IGF2-INS-TH
region of human chromosome 11. Hum Genet. 2002;110:
173– 81.
561. Le Stunff C, Fallin D, Bougneres P. Paternal transmission
of the very common class I INS VNTR alleles predisposes to
childhood obesity. Nat Genet. 2001;29:96 –9.
428
OBESITY RESEARCH Vol. 12 No. 3 March 2004
562. O’Dell SD, Bujac SR, Miller GJ, Day IN. Associations of
IGF2 ApaI RFLP and INS VNTR class I allele size with
obesity. Eur J Hum Genet. 1999;7:821–7.
563. Weaver JU, Kopelman PG, Hitman GA. Central obesity
and hyperinsulinaemia in women are associated with polymorhism in the 5⬘ flanking region of the human insulin gene.
Eur J Clin Invest. 1992;22:265–70.
564. Zee RY, Lou YK, Morris BJ. Insertion variant in intron 9,
but not microsatellite in intron 2, of the insulin receptor gene
is associated with essential hypertension. J Hypertens Suppl.
1994;12:13–22.
565. Krempler F, Hell E, Winkler C, Breban D, Patsch W.
Plasma leptin levels: interaction of obesity with a common
variant of insulin receptor substrate-1. Arterioscler Thromb
Vasc Biol. 1998;18:1686 –90.
566. Lei H, Coresh J, Shuldiner A, Boerwinkle E, Brancati F.
Variants of the insulin receptor substrate-1 and fatty acid
binding protein 2 genes and the risk of type 2 diabetes,
obesity, and hyperinsulinemia in African-Americans: the
Atherosclerosis Risk in Communities Study. Diabetes. 1999;
48:1868 –72.
567. Griffiths LR, Nyhold DR, Curtain RP, Gaffney PT, Morris BJ. Cross-sectional study of a microsatellite marker in the
low density lipoprotein receptor gene in obese normotensives. Clin Exp Pharmacol Physiol. 1995;22:496 – 8.
568. Mattevi VS, Coimbra CE, Santos RV, Salzano FM, Hutz
MH. Association of the low-density lipoprotein receptor
gene with obesity in Native American populations. Hum
Genet. 2000;106:546 –52.
569. Rutherford S, Nyholt D, Curtain R, et al. Association of a
low density lipoprotein receptor microsatellite variant with
obesity. Int J Obes Relat Metab Disord. 1997;21:1032–7.
570. Zee RYL, Griffiths LR, Morris BJ. Marked association of
a RFLP for the low density lipoprotein receptor gene with
obesity in essential hypertensives. Biochem Biophys Res
Commun. 1992;189:965–71.
571. Zee RYL, Schrader AP, Robinson BG, Griffiths LR,
Morris BJ. Association of HincII RFLP of low density
lipoprotein receptor gene with obesity in essential hypertensives. Clin Genet. 1995;47:118 –21.
572. Butler MG, Hedges L, Hovis CL, Feurer ID. Genetic
variants of the human obesity (OB) gene in subjects with and
without Prader-Willi syndrome: comparison with body mass
index and weight. Clin Genet. 1998;54:385–93.
573. Hager J, Clement K, Francke S, et al. A polymorphism in
the 5⬘ untranslated region of the human ob gene is associated
with low leptin levels. Int J Obes Relat Metab Disord.
1998;22:200 –5.
574. Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P. A
polymorphism in the leptin promoter region (-2548 G/A)
influences gene expression and adipose tissue secretion of
leptin. Horm Metab Res. 2002;34:355–9.
575. Le Stunff C, Le Bihan C, Schork NJ, Bougneres P. A
common promoter variant of the leptin gene is associated
with changes in the relationship between serum leptin and fat
mass in obese girls. Diabetes. 2000;49:2196 –200.
576. Li WD, Reed DR, Lee JH, et al. Sequence variants in the 5⬘
flanking region of the leptin gene are associated with obesity
in women. Ann Hum Genet. 1999;63:227–34.
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
577. Mammes O, Betoulle D, Aubert R, et al. Novel polymorphisms in the 5⬘ region of the LEP gene: association with
leptin levels and response to low-calorie diet in human obesity. Diabetes. 1998;47:487–9.
578. Oksanen L, Ohman M, Heiman M, et al. Markers for the
gene ob and serum leptin levels in human morbid obesity.
Hum Genet. 1997;99:559 – 64.
579. Shintani M, Ikegami H, Yamato E, et al. A novel microsatellite polymorphism in the human OB gene: a highly
polymorphic marker for linkage analysis. Diabetologia.
1996;39:1398 – 401.
580. Chagnon YC, Wilmore JH, Borecki IB, et al. Associations
between the leptin receptor gene and adiposity in middleaged Caucasian males from the HERITAGE family study.
J Clin Endocrinol Metab. 2000;85:29 –34.
581. Chagnon YC, Chung WK, Perusse L, Chagnon M, Leibel
RL, Bouchard C. Linkages and associations between the
leptin receptor (LEPR) gene and human body composition in
the Quebec Family Study. Int J Obes Relat Metab Disord.
1999;23:278 – 86.
582. da Silva B, Gapstur SM, Achenbach YH, et al. Lack of
association between the -308 polymorphism of the tumor
necrosis factor-alpha gene and the insulin resistance syndrome. J Investig Med. 2000;48:236 – 44.
583. Mammes O, Aubert R, Betoulle D, et al. LEPR gene
polymorphisms: associations with overweight, fat mass and
response to diet in women. Eur J Clin Invest. 2001;31:398 –
404.
584. Mattevi VS, Zembrzuski VM, Hutz MH. Association analysis of genes involved in the leptin-signaling pathway with
obesity in Brazil. Int J Obes Relat Metab Disord. 2002;26:
1179 – 85.
585. Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore AI.
A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in
postmenopausal Caucasian women. Hum Genet. 2001;108:
233– 6.
586. Rosmond R, Chagnon YC, Holm G, et al. Hypertension in
obesity and the leptin receptor gene locus. J Clin Endocrinol
Metab. 2000;85:3126 –31.
587. Roth H, Korn T, Rosenkranz K, et al. Transmission disequilibrium and sequence variants at the leptin receptor gene
in extremely obese German children and adolescents. Hum
Genet. 1998;103:540 – 6.
588. Thompson DB, Ravussin E, Bennett PH, Bogardus C.
Structure and sequence variation at the human leptin receptor
gene in lean and obese Pima Indians. Hum Mol Genet.
1997;6:675–9.
589. Wauters M, Mertens I, Chagnon M, et al. Polymorphisms
in the leptin receptor gene, body composition and fat distribution in overweight and obese women. Int J Obes Relat
Metab Disord. 2001;25:714 –20.
590. Yiannakouris N, Yannakoulia M, Melistas L, Chan JL,
Klimis-Zacas D, Mantzoros CS. The Q223R polymorphism
of the leptin receptor gene is significantly associated with
obesity and predicts a small percentage of body weight and
body composition variability. J Clin Endocrinol Metab.
2001;86:4434 –9.
591. Garenc C, Perusse L, Chagnon YC, et al. The hormonesensitive lipase gene and body composition: the HERITAGE
Family Study. Int J Obes Relat Metab Disord. 2002;26:
220 –7.
592. Hoffstedt J, Arner P, Schalling M, et al. A common
hormone-sensitive lipase i6 gene polymorphism is associated
with decreased human adipocyte lipolytic function. Diabetes.
2001;50:2410 –3.
593. Lavebratt C, Ryden M, Schalling M, Sengul S, Ahlberg S,
Hoffstedt J. The hormone-sensitive lipase i6 gene polymorphism and body fat accumulation. Eur J Clin Invest. 2002;
32:938 – 42.
594. Magre J, Laurell H, Fizames C, et al. Human hormonesensitive lipase. Genetic mapping, identification of a new
dinucleotide repeat, and association with obesity and
NIDDM. Diabetes. 1998;47:284 – 6.
595. Pihlajamaki J, Valve R, Karjalainen L, Karhapaa P,
Vauhkonen I, Laakso M. The hormone sensitive lipase
gene in familial combined hyperlipidemia and insulin resistance. Eur J Clin Invest. 2001;31:302– 8.
596. Hegele RA, Cao H, Huff MW, Anderson CM. LMNA
R482Q mutation in partial lipodystrophy associated with
reduced plasma leptin concentration. J Clin Endocrinol
Metab. 2000;85:3089 –93.
597. Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJ,
Anderson CM. Genetic variation in LMNA modulates
plasma leptin and indices of obesity in aboriginal canadians.
Physiol Genomics. 2000;3:39 – 44.
598. Hegele RA, Anderson CM, Wang J, Jones DC, Cao H.
Association between nuclear lamin A/C R482Q mutation and
partial lipodystrophy with hyperinsulinemia, dyslipidemia,
hypertension, and diabetes. Genome Res. 2000;10:652– 8.
599. Hegele RA, Huff MW, Young TK. Common genomic
variation in LMNA modulates indexes of obesity in Inuit.
J Clin Endocrinol Metab. 2001;86:2747–51.
600. Garenc C, Perusse L, Bergeron J, et al. Evidence of LPL
gene-exercise interaction for body fat and LPL activity: the
HERITAGE Family Study. J Appl Physiol. 2001;91:1334 –
40.
601. Jemaa R, Tuzet S, Portos C, Betoulle D, Apfelbaum M,
Fumeron F. Lipoprotein lipase gene polymorphisms: associations with hypertriglyceridemia and body mass index in
obese people. Int J Obes Relat Metab Disord. 1995;19:
270 – 4.
602. Boucher N, Lanouette CM, Larose M, Perusse L, Bouchard C, Chagnon YC. A ⫹2138InsCAGACC polymorphism of the melanocortin receptor 3 gene is associated in
human with fat level and partitioning in interaction with body
corpulence. Mol Med. 2002;8:158 – 65.
603. Chagnon YC, Chen WJ, Perusse L, et al. Linkage and
association studies between the melanocortin receptors 4 and
5 genes and obesity-related phenotypes in the Quebec Family
Study. Mol Med. 1997;3:663–73.
604. Rosmond R, Chagnon M, Bouchard C, Björntorp P. A
missense mutation in the human melanocortin-4 receptor
gene in relation to abdominal obesity and salivary cortisol.
Diabetologia. 2001;44:1335– 8.
OBESITY RESEARCH Vol. 12 No. 3 March 2004
429
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
605. Bray MS, Boerwinkle E, Hanis CL. Sequence variation
within the neuropeptide Y gene and obesity in Mexican
Americans. Obes Res. 2000;8:219 –26.
606. Karvonen MK, Koulu M, Pesonen U, et al. Leucine 7 to
proline 7 polymorphism in the preproneuropeptide Y is associated with birth weight and serum triglyceride concentration in preschool aged children. J Clin Endocrinol Metab.
2000;85:1455– 60.
607. Jenkinson CP, Cray K, Walder K, Herzog H, Ravussin E,
Hanson R. Novel polymorphisms in the neuropeptide-Y Y5
receptor associated with obesity in Pima Indians. Int J Obes
Relat Metab Disord. 2000;24:580 – 4.
608. Nishigori H, Tomura H, Tonooka N, et al. Mutations in the
small heterodimer partner gene are associated with mild
obesity in Japanese subjects. Proc Natl Acad Sci U S A.
2001;98:575– 80.
609. Buemann B, Vohl MC, Chagnon M, et al. Abdominal
visceral fat is associated with a BclI restriction fragment
length polymorphism at the glucocorticoid receptor gene
locus. Obes Res. 1997;5:186 –92.
610. Dobson MG, Redfern CP, Unwin N, Weaver JU. The
N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and
diabetes mellitus. J Clin Endocrinol Metab. 2001;86:
2270 – 4.
611. Rosmond R, Chagnon YC, Holm G, et al. A glucocorticoid
receptor gene marker is associated with abdominal obesity,
leptin, and dysregulation of the hypothalamic-pituitary-adrenal axis. Obes Res. 2000;8:211– 8.
612. Ukkola O, Perusse L, Chagnon YC, Despres JP, Bouchard C. Interactions among the glucocorticoid receptor,
lipoprotein lipase and adrenergic receptor genes and abdominal fat in the Quebec Family Study. Int J Obes Relat Metab
Disord. 2001;25:1332–9.
613. Ukkola O, Rosmond R, Tremblay A, Bouchard C. Glucocorticoid receptor Bcl I variant is associated with an increased atherogenic profile in response to long-term overfeeding. Atherosclerosis. 2001;157:221– 4.
614. del Giudice EM, Cirillo G, Santoro N, et al. Molecular
screening of the proopiomelanocortin (POMC) gene in Italian obese children: report of three new mutations. Int J Obes
Relat Metab Disord. 2001;25:61–7.
615. Hixson J, Almasy L, Cole S, et al. Normal variation in
leptin levels is associated with polymorphisms in the proopiomelanocortin gene, POMC. J Clin Endocrinol Metab.
1999;84:3187–91.
616. Busch C, Ramdath D, Ramsewak S, Hegele R. Association of PON2 variation with birth weight in Trinidadian
neonates of South Asian ancestry. Pharmacogenetics.
1999;9:351– 6.
617. Evans D, Aberle J, Wendt D, Wolf A, Beisiegel U,
Mann WA. A polymorphism, L162V, in the peroxisome
proliferator-activated receptor alpha (PPARalpha) gene is
associated with lower body mass index in patients with
non-insulin-dependent diabetes mellitus. J Mol Med.
2001;79:198 –204.
618. Cole SA, Mitchell BD, Hsueh WC, et al. The Pro12Ala
variant of peroxisome proliferator-activated receptor-gam430
OBESITY RESEARCH Vol. 12 No. 3 March 2004
619.
620.
621.
622.
623.
624.
625.
626.
627.
628.
629.
630.
ma2 (PPAR-gamma2) is associated with measures of obesity
in Mexican Americans. Int J Obes Relat Metab Disord.
2000;24:522– 4.
Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor
activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998;20:284 –7.
Ek J, Urhammer SA, Sorensen TI, Andersen T, Auwerx
J, Pedersen O. Homozygosity of the Pro12Ala variant of
the peroxisome proliferation- activated receptor-gamma2
(PPAR-gamma2): divergent modulating effects on body
mass index in obese and lean Caucasian men. Diabetologia.
1999;42:892–5.
Gonzalez Sanchez JL, Serrano Rios M, Fernandez Perez
C, Laakso M, Martinez Larrad MT. Effect of the
Pro12Ala polymorphism of the peroxisome proliferator- activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population. Eur J
Endocrinol. 2002;147:495–501.
Hasstedt SJ, Ren QF, Teng K, Elbein SC. Effect of the
peroxisome proliferator-activated receptor-gamma 2 pro(12)ala
variant on obesity, glucose homeostasis, and blood pressure
in members of familial type 2 diabetic kindreds. J Clin
Endocrinol Metab. 2001;86:536 – 41.
Lindi V, Sivenius K, Niskanen L, Laakso M, Uusitupa
MI. Effect of the Pro12Ala polymorphism of the PPARgamma2 gene on long-term weight change in Finnish nondiabetic subjects. Diabetologia. 2001;44:925– 6.
Lindi VI, Uusitupa MI, Lindstrom J, et al. Association of
the Pro12Ala polymorphism in the PPAR-gamma2 gene with
3-year incidence of type 2 diabetes and body weight change
in the Finnish Diabetes Prevention Study. Diabetes. 2002;
51:2581– 6.
Meirhaeghe A, Fajas L, Helbecque N, et al. Impact of
the peroxisome proliferator activated receptor gamma2
Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus. Int J Obes Relat Metab
Disord. 2000;24:195–9.
Meirhaeghe A, Fajas L, Helbecque N, et al. A genetic
polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese
humans. Hum Mol Genet. 1998;7:435– 40.
Nicklas BJ, van Rossum EF, Berman DM, Ryan AS,
Dennis KE, Shuldiner AR. Genetic variation in the peroxisome proliferator-activated receptor-gamma2 gene (Pro12Ala)
affects metabolic responses to weight loss and subsequent
weight regain. Diabetes. 2001;50:2172– 6.
Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn
CR. Obesity associated with a mutation in a genetic regulator
of adipocyte differentiation. N Engl J Med. 1998;339:953–9.
Vaccaro O, Mancini FP, Ruffa G, Sabatino L, Colantuoni
V, Riccardi G. Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and severe obesity: a case-control study. Int J Obes Relat Metab
Disord. 2000;24:1195–9.
Valve R, Sivenius K, Miettinen R, et al. Two polymorphisms in the peroxisome proliferator-activated receptor-
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
631.
632.
633.
634.
635.
636.
637.
638.
639.
640.
641.
642.
643.
644.
645.
gamma gene are associated with severe overweight among
obese women. J Clin Endocrinol Metab. 1999;84:3708 –
12.
Esterbauer H, Oberkofler H, Linnemayr V, et al. Peroxisome proliferator-activated receptor-gamma coactivator-1
gene locus: associations with obesity indices in middle-aged
women. Diabetes. 2002;51:1281– 6.
Engert JC, Vohl MC, Williams SM, et al. 5⬘ flanking
variants of resistin are associated with obesity. Diabetes.
2002;51:1629 –34.
Iwai N, Katsuya T, Mannami T, et al. Association between
SAH, an acyl-CoA synthetase gene, and hypertriglyceridemia, obesity, and hypertension. Circulation. 2002;105:41–7.
Acton S, Osgood D, Donoghue M, et al. Association of
polymorphisms at the SR-BI gene locus with plasma lipid
levels and body mass index in a white population. Arterioscler Thromb Vasc Biol. 1999;19:1734 – 43.
Hoffstedt J, Andersson IL, Persson L, Isaksson B, Arner
P. The common -675 4G/5G polymorphism in the plasminogen activator inhibitor -1 gene is strongly associated with
obesity. Diabetologia. 2002;45:584 –7.
Lin WH, Chiu KC, Chang HM, Lee KC, Tai TY, Chuang
LM. Molecular scanning of the human sorbin and SH3domain-containing-1 (SORBS1) gene: positive association
of the T228A polymorphism with obesity and type 2 diabetes. Hum Mol Genet. 2001;10:1753– 60.
Brand E, Schorr U, Kunz I, et al. Tumor necrosis factoralpha-308 G/A polymorphism in obese Caucasians. Int J
Obes Relat Metab Disord. 2001;25:581–5.
Dalziel B, Gosby AK, Richman RM, Bryson JM, Caterson ID. Association of the TNF-alpha -308 G/A promoter
polymorphism with insulin resistance in obesity. Obes Res.
2002;10:401–7.
Fernandez-Real JM, Gutierrez C, Ricart W, et al. The
TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and
increased serum leptin levels. Diabetes. 1997;46:1468 –
72.
Herrmann S, Ricard S, Nicaud V, et al. Polymorphisms of
the tumour necrosis factor-alpha gene, coronary heart disease
and obesity. Eur J Clin Invest. 1998;28:59 – 66.
Hoffstedt J, Eriksson P, Hellstrom L, Rossner S, Ryden
M, Arner P. Excessive fat accumulation is associated with
the TNF alpha-308 G/A promoter polymorphism in women
but not in men. Diabetologia. 2000;43:117–20.
Kamizono S, Yamada K, Seki N, et al. Susceptible locus
for obese type 2 diabetes mellitus in the 5⬘-flanking region of
the tumor necrosis factor-alpha gene. Tissue Antigens. 2000;
55:449 –52.
Norman RA, Bogardus C, Ravussin E. Linkage between
obesity and a marker near the tumor necrosis factor-A locus
in Pima Indians. J Clin Invest. 1995;96:158 – 62.
Pausova Z, Deslauriers B, Gaudet D, et al. Role of tumor
necrosis factor-alpha gene locus in obesity and obesity-associated hypertension in French Canadians. Hypertension.
2000;36:14 –9.
Fernandez-Real JM, Vendrell J, Ricart W, et al. Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is
associated with obesity, leptin levels, and insulin resistance
646.
647.
648.
649.
650.
651.
652.
653.
654.
655.
656.
657.
658.
659.
in young subjects and diet-treated type 2 diabetic patients.
Diabetes Care. 2000;23:831–7.
Philibert R, Caspers K, Langbehn D, et al. The association
of a HOPA polymorphism with major depression and phobia.
Compr Psychiatry. 2002;43:404 –10.
Fumeron F, Durack-Bown I, Betoulle D, et al. Polymorphisms of uncoupling protein (UCP) and beta 3 adrenoreceptor genes in obese people submitted to a low
calorie diet. Int J Obes Relat Metab Disord. 1996;20:
1051– 4.
Heilbronn LK, Kind KL, Pancewicz E, Morris
AM, Noakes M, Clifton PM. Association of -3826 G
variant in uncoupling protein-1 with increased BMI in
overweight Australian women. Diabetologia. 2000;43:
242– 4.
Kogure A, Yoshida T, Sakane N, Umekawa T,
Takakura Y, Kondo M. Synergic effect of polymorphisms in uncoupling protein 1 and beta3- adrenergic
receptor genes on weight loss in obese Japanese. Diabetologia. 1998;41:1399.
Oppert JM, Vohl MC, Chagnon M, et al. DNA polymorphism in the uncoupling protein (UCP) gene and human body
fat. Int J Obes Relat Metab Disord. 1994;18:526 –31.
Ukkola O, Tremblay A, Sun G, Chagnon YC, Bouchard
C. Genetic variation at the uncoupling protein 1, 2 and 3 loci
and the response to long-term overfeeding. Eur J Clin Nutr.
2001;55:1008 –15.
Astrup A, Toubro S, Dalgaard LT, Urhammer SA, Sorensen TIA, Pedersen O. Impact of the v/v 55 polymorphism of the uncoupling protein 2 gene on 24-h energy
expenditure and substrate oxidation. Int J Obes Relat Metab
Disord. 1999;23:1030 – 4.
Cassell PG, Neverova M, Janmohamed S, et al. An uncoupling protein 2 gene variant is associated with a raised
body mass index but not Type II diabetes. Diabetologia.
1999;42:688 –92.
Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP2 is associated
with decreased risk of obesity in middle-aged humans. Nat
Genet. 2001;28:178 – 83.
Evans D, Minouchehr S, Hagemann G, et al. Frequency of
and interaction between polymorphisms in the beta3-adrenergic receptor and in uncoupling proteins 1 and 2 and obesity
in Germans. Int J Obes Relat Metab Disord. 2000;24:1239 –
45.
Evans D, Wolf AM, Nellessen U, et al. Association between
polymorphisms in candidate genes and morbid obesity. Int J
Obes Relat Metab Disord. 2001;25:S19 –21.
Nordfors L, Heimburger O, Lonnqvist F, et al. Fat tissue
accumulation during peritoneal dialysis is associated with a
polymorphism in uncoupling protein 2. Kidney Int. 2000;57:
1713–9.
Walder K, Norman R, Hanson R, et al. Association between uncoupling protein polymorphisms (UCP2-UCP3) and
energy metabolism obesity in Pima Indians. Hum Mol Genet.
1998;7:1431–5.
Yanovski JA, Diament AL, Sovik KN, et al. Associations
between uncoupling protein 2, body composition, and resting
OBESITY RESEARCH Vol. 12 No. 3 March 2004
431
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
660.
661.
662.
663.
664.
665.
666.
667.
668.
669.
670.
671.
672.
673.
674.
432
energy expenditure in lean and obese African American,
white, and Asian children. Am J Clin Nutr. 2000;71:1405–20.
Argyropoulos G, Brown AM, Willi SM, et al. Effects of
mutations in the human uncoupling protein 3 gene on the
respiratory quotient and fat oxidation in severe obesity and
type 2 diabetes. J Clin Invest. 1998;102:1345–51.
Cassell PG, Saker PJ, Huxtable SJ, et al. Evidence that
single nucleotide polymorphism in the uncoupling protein 3
(UCP3) gene influences fat distribution in women of European and Asian origin. Diabetologia. 2000;43:1558 – 64.
Halsall D, Luan J, Saker P, et al. Uncoupling protein 3
genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a
UK Caucasian population. Int J Obes Relat Metab Disord.
2001;25:472–7.
Kimm SY, Glynn NW, Aston CE, et al. Racial differences
in the relation between uncoupling protein genes and resting
energy expenditure. Am J Clin Nutr. 2002;75:714 –9.
Lanouette CM, Giacobino JP, Perusse L, et al. Association between uncoupling protein 3 gene and obesity-related
phenotypes in the Quebec Family Study. Mol Med. 2001;7:
433– 41.
Lanouette CM, Chagnon YC, Rice T, et al. Uncoupling
protein 3 gene is associated with body composition changes
with training in HERITAGE study. J Appl Physiol. 2002;92:
1111– 8.
Otabe S, Clement K, Dina C, et al. A genetic variation in
the 5⬘ flanking region of the UCP3 gene is associated with
body mass index in humans in interaction with physical
activity. Diabetologia. 2000;43:245–9.
Otabe S, Clement K, Dubois S, et al. Mutation screening
and association studies of the human uncoupling protein 3
gene in normoglycemic and diabetic morbidly obese patients.
Diabetes. 1999;48:206 – 8.
Yanagisawa Y, Hasegawa K, Dever GJ, et al. Uncoupling
protein 3 and peroxisome proliferator-activated receptor
gamma2 contribute to obesity and diabetes in palauans. Biochem Biophys Res Commun. 2001;281:772– 8.
Deng HW, Deng H, Liu YJ, et al. A genomewide linkage
scan for quantitative-trait loci for obesity phenotypes. Am J
Hum Genet. 2002;70:1138 –51.
Stone S, Abkevich V, Hunt SC, et al. A major predisposition locus for severe obesity, at 4p15–p14. Am J Hum Genet.
2002;70:1459 – 68.
Wilson AF, Elston RC, Tran LD, Siervogel RM. Use of
the robust sib-pair method to screen for single-locus, multiple-locus, and pleiotropic effects: application to traits related
to hypertension. Am J Hum Genet. 1991;48:862–72.
Chagnon YC, Perusse L, Lamothe M, et al. Suggestive
linkages between markers on human 1p32–p22 and body fat
and insulin levels in the Quebec Family Study. Obes Res.
1997;5:115–21.
Bray MS, Boerwinkle E, Hanis CL. Linkage analysis of
candidate obesity genes among the Mexican-American population of Starr County, Texas. Genet Epidemiol. 1999;16:
397– 411.
van der Kallen CJ, Cantor RM, van Greevenbroek MM,
et al. Genome scan for adiposity in Dutch dyslipidemic
families reveals novel quantitative trait loci for leptin, body
OBESITY RESEARCH Vol. 12 No. 3 March 2004
675.
676.
677.
678.
679.
680.
681.
682.
683.
684.
685.
686.
687.
688.
689.
mass index and soluble tumor necrosis factor receptor superfamily 1A. Int J Obes Relat Metab Disord. 2000;24:1381–
91.
Norman R, Tataranni P, Pratley R, et al. Autosomal
genomic scan for loci linked to obesity and energy metabolism in Pima Indians. Am J Hum Genet. 1998;62:659 – 68.
Perusse L, Rice T, Chagnon Y, et al. A genome-wide scan
for abdominal fat assessed by computed tomography in the
Quebec Family Study. Diabetes. 2001;50:614 –21.
Feitosa MF, Borecki IB, Rich SS, et al. Quantitative-trait
loci influencing body-mass index reside on chromosomes 7
and 13: the National Heart, Lung, and Blood Institute Family
Heart Study. Am J Hum Genet. 2002;70:72– 82.
Weyer C, Wolford JK, Hanson RL, et al. Subcutaneous
abdominal adipocyte size, a predictor of type 2 diabetes, is
linked to chromosome 1q21– q23 and is associated with a
common polymorphism in LMNA in Pima Indians. Mol
Genet Metab. 2001;72:231– 8.
Bailey-Wilson JE, Wilson AF, Bamba V. Linkage analysis
in a large pedigree ascertained due to essential familial
hypercholesterolemia. Genet Epidemiol. 1993;10:665–9.
Delplanque J, Barat-Houari M, Dina C, et al. Linkage and
association studies between the proopiomelanocortin
(POMC) gene and obesity in caucasian families. Diabetologia. 2000;43:1554 –7.
Comuzzie AG, Funahashi T, Sonnenberg G, et al. The
genetic basis of plasma variation in adiponectin, a global
endophenotype for obesity and the metabolic syndrome.
J Clin Endocrinol Metab. 2001;86:4321–5.
Rotimi CN, Comuzzie AG, Lowe WL, Luke A, Blangero
J, Cooper RS. The quantitative trait locus on chromosome 2
for serum leptin levels is confirmed in African-Americans.
Diabetes. 1999;48:643– 4.
Rice T, Chagnon YC, Perusse L, et al. A genomewide
linkage scan for abdominal subcutaneous and visceral fat in
black and white families: The HERITAGE Family Study.
Diabetes. 2002;51:848 –55.
Wu X, Cooper RS, Borecki I, et al. A combined analysis of
genomewide linkage scans for body mass index from the
National Heart, Lung, and Blood Institute Family Blood
Pressure Program. Am J Hum Genet. 2002;70:1247–56.
Norman RA, Thompson DB, Foroud T, et al. Genome
wide search for genes influencing percent body fat in Pima
Indians: suggestive linkage at chromosome 11q21– q22.
Am J Hum Genet. 1997;60:166 –73.
Zhu X, Cooper RS, Luke A, et al. A genome-wide scan for
obesity in African-Americans. Diabetes. 2002;51:541– 4.
Borecki IB, Rice T, Pérusse L, Bouchard C, Rao DC. An
exploratory investigation of genetic linkage with obesity
phenotypes: the Quebec Family Study. Obes Res. 1994;2:
213–9.
Lindsay RS, Kobes S, Knowler WC, Bennett PH, Hanson
RL. Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in
Pima Indians. Diabetes. 2001;50:2850 –7.
Clement K, Dina C, Basdevant A, et al. A sib-pair analysis
study of 15 candidate genes in French families with morbid
obesity: indication for linkage with islet 1 locus on chromosome 5q. Diabetes. 1999;48:398 – 402.
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
690. Steinle NI, Hsueh WC, Snitker S, et al. Eating behavior in
the Old Order Amish: heritability analysis and a genomewide linkage analysis. Am J Clin Nutr. 2002;75:1098 –106.
691. Walder K, Morris C, Ravussin E. A polymorphism in the
gene encoding CART is not associated with obesity in Pima
Indians. Int J Obes Relat Metab Disord. 2000;24:520 –1.
692. Arya R, Blangero J, Williams K, et al. Factors of insulin
resistance syndrome-related phenotypes are linked to genetic
locations on chromosomes 6 and 7 in nondiabetic MexicanAmericans. Diabetes. 2002;51:841–7.
693. Chagnon YC, Borecki IB, Perusse L, et al. Genome-wide
search for genes related to the fat-free body mass in the
Quebec family study. Metabolism. 2000;49:203–7.
694. Clement K, Garner C, Hager J, et al. Indication for linkage
of the human OB gene region with extreme obesity. Diabetes. 1996;45:687–90.
695. Duggirala R, Stern MP, Mitchell BD, et al. Quantitative
variation in obesity-related traits and insulin precursors
linked to the OB gene region on human chromosome 7. Am J
Hum Genet. 1996;59:694 –703.
696. Onions K, Hunt S, Rutkowski M, et al. Genetic markers
at the leptin (OB) locus are not significantly linked to hypertension in African Americans. Hypertension. 1998;31:
1230 – 4.
697. Reed DR, Ding Y, Xu W, Cather C, Green ED, Price RA.
Extreme obesity may be linked to markers flanking the
human OB gene. Diabetes. 1996;45:691– 4.
698. Roth H, Hinney A, Ziegler A, et al. Further support for
linkage of extreme obesity to the obese gene in a study group
of obese children and adolescents. Exp Clin Endocrinol
Diabetes. 1997;105:341– 4.
699. Lapsys NM, Furler SM, Moore KR, et al. Relationship
of a novel polymorphic marker near the human obese
(OB) gene to fat mass in healthy women. Obes Res.
1997;5:430 –3.
700. Hsueh WC, Mitchell BD, Schneider JL, et al. Genomewide scan of obesity in the Old Order Amish. J Clin Endocrinol Metab. 2001;86:1199 –205.
701. Mitchell B, Cole S, Comuzzie A, et al. A quantitative trait
locus influencing BMI maps to the region of the beta-3
adrenergic receptor. Diabetes. 1999;48:1863–7.
702. Chagnon YC, Rice T, Perusse L, et al. Genomic scan for
genes affecting body composition before and after training
in Caucasians from HERITAGE. J Appl Physiol. 2001;90:
1777– 87.
703. Hinney A, Ziegler A, Oeffner F, et al. Independent confirmation of a major locus for obesity on chromosome 10.
J Clin Endocrinol Metab. 2000;85:2962–5.
704. Price RA, Li WD, Bernstein A, et al. A locus affecting
obesity in human chromosome region 10p12. Diabetologia.
2001;44:363– 6.
705. Bouchard C, Perusse L, Chagnon YC, Warden C, Ricquier D. Linkage between markers in the vicinity of the
uncoupling protein 2 gene and resting metabolic rate in
humans. Hum Mol Genet. 1997;6:1887–9.
706. Hanson RL, Ehm MG, Pettitt DJ, et al. An autosomal
genomic scan for loci linked to type II diabetes mellitus and
body-mass index in Pima Indians. Am J Hum Genet. 1998;
63:1130 – 8.
707. Ohman M, Oksanen L, Kaprio J, et al. Genome-wide scan
of obesity in Finnish sibpairs reveals linkage to chromosome
Xq24. J Clin Endocrinol Metab. 2000;85:3183–90.
708. Hunt SC, Abkevich V, Hensel CH, et al. Linkage of body
mass index to chromosome 20 in Utah pedigrees. Hum
Genet. 2001;109:279 – 85.
709. Lee JH, Reed DR, Li WD, et al. Genome scan for human
obesity and linkage to markers in 20q13. Am J Hum Genet.
1999;64:196 –209.
710. Price RA, Kilker R, Li WD. An X-chromosome scan reveals a locus for fat distribution in chromosome region
Xp21–22. Diabetes. 2002;51:1989 –91.
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Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map
Gene or locus
Name
Location
A
A4GALT
ABCC8
ACACB
ACE
ACH
ACP1
ADA
ADRA2A
ADRA2B
ADRB1
ADRB2
ADRB3
AGPAT2
AGRP
AGS
AGT
AHO
AHO2
AK1
ALMS1
ANCR
ANMA
APM1
APOA1
APOA2
APOA4
APOB
APOC1
APOD
APOE
AR
ASIP
ATP1A2
ATP1B1
ATRN
alpha 1,4-galactosyltransferase (P1 blood group) (also referred to before as P1)
ATP-binding cassette, sub-family C (CFTR/MRP), member 8 (sulfonylurea receptor)
(also referred to before as SUR1)
acetyl-Coenzyme A carboxylase beta
angiotensin I converting enzyme (peptidyl-dipeptidase A) 1
achondroplasia (thanatophoric dwarfism)
acid phosphatase 1, soluble
adenosine deaminase
adrenergic, alpha-2A-, receptor
adrenergic, alpha-2B-, receptor
adrenergic, beta-1-, receptor
adrenergic, beta-2-, receptor, surface
adrenergic, beta-3-, receptor
1-acylglycerol-3-phosphate O-acyltransferase 2 (lysophosphatidic acid
acyltransferase, beta) (Bernardinelli-Seip congenital lipodystrophy 1)
agouti related protein homolog (mouse)
Angelman syndrome with obesity
angiotensinogen [serine (or cysteine) proteinase inhibitor, clade A (alpha-1
antiproteinase, antitrypsin), member 8]
Albright hereditary osteodystrophy
Albright hereditary osteodystrophy 2
adenylate kinase 1
Alstrom syndrome 1
Angelman syndrome chromosome region
anisomastia (with obesity)
adipose most abundant gene transcript 1
apolipoprotein A–I
apolipoprotein A–II
apolipoprotein A–IV
apolipoprotein B [including Ag(x) antigen]
apolipoprotein C–I
apolipoprotein D
apolipoprotein E
androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and
bulbar muscular atrophy; Kennedy disease)
agouti signaling protein, nonagouti homolog (mouse)
ATPase, Na⫹/K⫹ transporting, alpha 2 (⫹) polypeptide
ATPase, Na⫹/K⫹ transporting, beta 1 polypeptide
attractin
22q13.31
11p15.1
12q24.1
17q24.1
4p16.3
2p25
20q13.12
10q25.3
2q11.2
10q26.11
5q31-q32
8p12-p11.2
9q34.3
16q22.1
15q11-q13
1q42.2
20q13.2
15q11-q13
9q34.13
2p13.1
15q11-q12
16q13-q21
3q28
11q23.3
1q23.1
11q23.3
2p24.2
19q13.2
3q26.2-qter
19q13.32
Xq11.2-q12
20q11.2-q12
1q23.1
1q23.3
20p13
B–C
BATF
BBS1
BBS2
BBS3
BBS4
434
basic leucine zipper transcription factor, ATF-like
Bardet-Biedl syndrome 1
Bardet-Biedl syndrome 2
Bardet-Biedl syndrome 3
Bardet-Biedl syndrome 4 (myosin IXA)
OBESITY RESEARCH Vol. 12 No. 3 March 2004
14q24.3
11q13.1
16q13
3p13-p12
15q22.33
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Appendix. (contents)
Gene or locus
BBS5
BBS6
BBS7
BF
BFLS
BRS3
BSCL1
BSCL2
BULN
C3
CAPN10
CART
CBFA2T1
CCKAR
CCKBR
CDGS1A
CEBPA
CEBPB
CHM
CHOD
CHRM3
CNTFR
COH1
COL8A2
CPE
CPHD
CYP19A1
CYP7A1
Name
Location
Bardet-Biedl syndrome 5
Bardet-Biedl syndrome 6 (MKKS)
Bardet-Biedl syndrome 7
B-factor, properdin
Borjeson-Forssman-Lehmann syndrome
bombesin-like receptor 3
Bernardinelli-Seip congenital lipodystrophy 1
Bernardinelli-Seip congenital lipodystrophy 2 (seipin)
bulimia nervosa, susceptibility to
complement component 3
calpain 10
cocaine- and amphetamine-regulated transcript
core-binding factor, runt domain, alpha subunit 2; translocated to, 1; cyclin Drelated
cholecystokinin A receptor
cholecystokinin B receptor
carbohydrate-deficient glycoprotein syndrome type 1a
CCAAT/enhancer binding protein (C/EBP), alpha
CCAAT/enhancer binding protein (C/EBP), beta
choroideremia (Rab escort protein 1)
choroideremia with deafness
cholinergic receptor, muscarinic 3
ciliary neurotrophic factor receptor
Cohen syndrome 1
collagen, type VIII, alpha 2
carboxypeptidase E
combined pituitary hormone deficiency
cytochrome P450, family 19, subfamily A, polypeptide 1
cytochrome P450, family 7, subfamily A, polypeptide 1
2q31
20p12.2
4q27
6p21.31
Xq26.3
Xq26-q28
9q34
11q13
10p14-p12.33
19p13.3
2q37.3
5q13.2
8q21.3
D component of complement (adipsin)
POU domain, class 3, transcription factor 4
diacylglycerol O-acyltransferase homolog 1 (mouse)
dopamine receptor D1
dopamine receptor D2
eukaryotic translation initiation factor 4E binding protein 1
ectonucleotide pyrophosphatase/phosphodiesterase 1
esterase D/formylglutathione hydrolase
estrogen receptor 1
fatty acid binding protein 2, intestinal
fatty acid binding protein 4, adipocyte
Fanconi-Bickel Syndrome (SLC2A2)
fibroblast growth factor 13
fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)
fragile X mental retardation 1
forkhead box C2 (MFH-1, mesenchyme forkhead 1)
19p13.3
Xq21.1
8q-ter
5q34-q35
11q23.2
8p12
6q23.1
13q14.11
6q25.1
4q27
8q21
3q26.1-q26.2
Xq26.3
4p16.3
Xq28
16q24.1
4p15.2-p15.1
11p15.4
16p13.3-p13.2
19q13.12
20q13.13
Xq21.2
Xq21.1-q21.2
1q41-q44
9p13.2
8q22.2
1p34.3
4q32
5q35.3
15q21
8q12.1
D–G
DF
DFN3
DGAT1
DRD1
DRD2
EIF4EBP1
ENPP1
ESD
ESR1
FABP2
FABP4
FBS
FGF13
FGFR3
FMR1
FOXC2
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Appendix. (continued)
Gene or locus
FPL
FPLD
FSHR
GCGR
GCK
GH1
GHRH
GHRHR
GHRL
GLO1
GNAS1
GNB3
GPC3
GPC4
GPD1
GPR24
GYPA
GYS1
Name
Location
familial partial lipodystrophy, non-Dunnigan (PPARGC1)
familial partial lipodystrophy, Dunnigan (LMNA)
follicle stimulating hormone receptor
glucagon receptor
glucokinase (hexokinase 4, maturity onset diabetes of the young 2)
growth hormone 1
growth hormone releasing hormone
growth hormone releasing hormone receptor
ghrelin precursor
glyoxalase I
GNAS complex locus
guanine nucleotide binding protein (G protein), beta polypeptide 3
glypican 3
glypican 4
glycerol-3-phosphate dehydrogenase 1 (soluble)
G protein-coupled receptor 24
glycophorin A (includes MN blood group)
glycogen synthase 1 (muscle)
4p15.1
1q23.1
2p21
17pter
7p13
17q24.2
20q11.2
7p14
3p25.3
6p21.2
20q13.32
12p13.31
Xq26.2
Xq26.1
12q13.2
22q13.3
4q31.1
19q13.33
hypocretin (orexin) neuropeptide precursor
huntingtin (Huntington disease)
high mobility group AT-hook 2
histamine receptor H1
hydroxysteroid (11-beta) dehydrogenase 1
hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1
heat shock 70kDa protein 1B
5-hydroxytryptamine (serotonin) receptor 1B
5-hydroxytryptamine (serotonin) receptor 2A
5-hydroxytryptamine (serotonin) receptor 2C
intercellular adhesion molecule 1 (CD54), human rhinovirus receptor
insulin-like growth factor 1 (somatomedin C)
insulin-like growth factor 1 receptor
insulin-like growth factor 2 (somatomedin A)
immunoglobulin heavy constant delta
immunoglobulin kappa constant
interleukin 1 receptor antagonist
interleukin 6 (interferon, beta 2)
interleukin 6 receptor
insulin
insulin receptor
imprinted in Prader-Willi syndrome
insulin resistance syndromes
insulin receptor substrate 1
insulin receptor substrate 2
ISL1 transcription factor, LIM/homeodomain, (islet-1)
Kell blood group
17q21
4p16.3
12q15
3p25
1q32-q41
1p11.2
6p21.31
6q14.1
13q14.11
Xq24
19p13.2
12q23.3
15q26.3
11p15.5
14q32.33
2p11.2
2q14.2
7p15.3
1q22
11p15.5
19p13.3
15q11.2
19p13.2
2q36.3
13q33.3
5q11.2
7q35
H–K
HCRT
HD
HMGA2
HRH1
HSD11B1
HSD3B1
HSPA1B
HTR1B
HTR2A
HTR2C
ICAM1
IGF1
IGF1R
IGF2
IGHD
IGKC
IL1RN
IL6
IL6R
INS
INSR
IPW
IRS
IRS1
IRS2
ISL1
KEL
436
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Appendix. (continued)
Gene or locus
Name
Location
L–O
LDLR
LEP
LEPR
LHB
LIPC
LIPE
LMNA
LPIN1
LPL
MACS2
MAGEL2
MAPK8IP1
MC3R
MC4R
MC5R
MEHMO
MGRN1
MKKS
MKRN3
MRXS11
MRXS7
MT1A
MT1B
MYO9A
NCOA3
NDN
NHLH2
NOS3
NPY
NPY5R
NR0B2
NR3C1
ORM1
low density lipoprotein receptor (familial hypercholesterolemia)
leptin (obesity homolog, mouse)
leptin receptor
luteinizing hormone beta polypeptide
lipase, hepatic
lipase, hormone-sensitive
lamin A/C
lipin 1
lipoprotein lipase
SAH family member, acyl-CoA synthetase for fatty acids
MAGE-like 2
mitogen-activated protein kinase 8 interacting protein 1
melanocortin 3 receptor
melanocortin 4 receptor
melanocortin 5 receptor
mental retardation, epileptic seizures, hypogonadism and genitalism, microcephaly
and obesity syndrome
mahogunin, ring finger 1
McKusick-Kaufman syndrome
makorin, ring finger protein, 3 (also referred to before as ZNF127)
mental retardation, X-linked, syndromic 11
mental retardation, X-linked, syndromic 7
metallothionein 1A (functional)
metallothionein 1B (functional)
myosin IXA
nuclear receptor coactivator 3
necdin homolog (mouse)
nescient helix loop helix 2
nitric oxide synthase 3 (endothelial cell)
neuropeptide Y
neuropeptide Y receptor Y5
nuclear receptor subfamily 0, group B, member 2
nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) (also
referred to before as GRL)
orosomucoid 1
19p13.2
7q32.2
1p31.3
19q13.32
15q21.3
19q13.31
1q23.1
2p21
8p21.3
16p12.3
15q11.2
11p11.2
20q13.2
18q21.32
18p11.21
Xp22.13-p21.1
proprotein convertase subtilisin/kexin type 1
phosphogluconate dehydrogenase
progesterone receptor
PHD finger protein 6
perilipin
pro-melanin-concentrating hormone
phosphomannomutase 2
phenylethanolamine N-methyltransferase
5q15
1p36.22
11q22.2
Xq26.3
15q26
12q23.3
16p13.2
17q21.2
16p13.3
20p12.2
15q11.2
Xq26-q27
Xp11.3-q22.1
16q13
16q13
15q22.33
20q13.13
15q11.2
1p13.1
7q36.1
7p15.3
4q32.2
1p35.3
5q31
9q33.1
P–R
PCSK1
PGD
PGR
PHF6
PLIN
PMCH
PMM2
PNMT
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The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Appendix. (continued)
Gene or locus
POMC
PON2
PPARA
PPARG
PPARGC1
PPCD
PPP1R3A
PPY
PRKAB2
PRKAR1A
PRKCQ
PROP1
PTPN1
PTPRB
PWCR
PWCR1
PWLS
PWLSX
PWS
RETN
Name
Location
proopiomelanocortin (adrenocorticotropin/beta-lipotropin/alpha-melanocyte
stimulating hormone/beta-melanocyte stimulating hormone/beta-endorphin)
paraoxonase 2
peroxisome proliferative activated receptor, alpha
peroxisome proliferative activated receptor, gamma
peroxisome proliferative activated receptor, gamma, coactivator 1
posterior polymorphous corneal dystrophy (VSX1)
protein phosphatase 1, regulatory (inhibitor) subunit 3A (glycogen and sarcoplasmic
reticulum binding subunit, skeletal muscle)
pancreatic polypeptide
protein kinase, AMP-activated, beta 2 non-catalytic subunit
protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific
extinguisher 1)
protein kinase C, theta
prophet of Pit1, paired-like homeodomain transcription factor
protein tyrosine phosphatase, non-receptor type 1
protein tyrosine phosphatase, receptor type, B
Prader-Willi syndrome chromosome region
Prader-Willi syndrome chromosome region 1
Prader-Willi-Like Syndrome (chr6)
Prader-Willi-Like Syndrome, X-linked
Prader-Willi syndrome chromosome region
resistin (also referred to before as FIZZ3)
2p24.1
SA hypertension-associated homolog (rat)
scavenger receptor class B, member 1 (also referred to before as CD36L1)
syndecan 1
serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminogen activator
inhibitor type 1), member 1
Simpson-Golabi-Behmel syndrome, type 1 (GPC3)
Simpson-Golabi-Behmel syndrome, type 2
single-minded homolog 1 (Drosophila)
solute carrier family 2 (facilitated glucose transporter), member 2
solute carrier family 6 (neurotransmitter transporter, GABA), member 1
solute carrier family 6 (neurotransmitter transporter, dopamine), member 3
small nuclear ribonucleoprotein polypeptide N
sorbin and SH3 domain containing 1 (also referred to before as SH3D5)
secreted protein, acidic, cysteine-rich (osteonectin)
sterol regulatory element binding transcription factor 1
signal transducer and activator of transcription 5A
serine/threonine kinase 25 (STE20 homolog, yeast)
T-box 3 (ulnar mammary syndrome)
transcription factor 1, hepatic; LF-B1, hepatic nuclear factor (HNF1), albumin
proximal factor
transcription factor 8 (represses interleukin 2 expression)
transforming growth factor, beta 1 (Camurati-Engelmann disease)
16p13.11
12q24.31
2p24.1
7q22.1
7q21.3
22q13.31
3p25.2
4p15.31
20p11.21
7q31.2
17q21
1q12
17q24.3
10p15.1
5q35.3
20q13.1-q13.2
12q15-q21
15q11-q12
15q11.2
6q16.2-q14
Xq23-q25
15q11-q13
19p13.3
S–T
SAH
SCARB1
SDC1
SERPINE1
SGBS1
SGBS2
SIM1
SLC2A2
SLC6A1
SLC6A3
SNRPN
SORBS1
SPARC
SREBF1
STAT5A
STK25
TBX3
TCF1
TCF8
TGFB1
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Xq26.2
Xp22
6q16.3
3q26.31
3p25-p24
5p15.33
15q12
10q24.1
5q33.1
17p11.2
17q11.2
2q37.3
12q24.21
12q24.31
10p11.23
19q13.31
The Human Obesity Gene Map: The 2003 Update, Snyder et al.
Appendix. (continued)
Gene or locus
TH
THRB
THRS
TNF
TNFRSF1B
TNRC11
TUB
Name
Location
tyrosine hydroxylase
thyroid hormone receptor, beta [erythroblastic leukemia viral (v-erb-a) oncogene
homolog 2, avian]
thyroid hormone resistance syndrome (THRB)
tumor necrosis factor (TNF superfamily, member 2)
tumor necrosis factor receptor superfamily, member 1B
trinucleotide repeat containing 11 (THR-associated protein, 230kDa subunit)
tubby homolog (mouse)
11p15.5
3p24.1
uncoupling protein 1 (mitochondrial, proton carrier)
uncoupling protein 2 (mitochondrial, proton carrier)
uncoupling protein 3 (mitochondrial, proton carrier)
ulnar mammary syndrome (TBX3)
vitamin D (1,25-dihydroxyvitamin D3) receptor
VGF nerve growth factor inducible
visual system homeobox 1 homolog, CHX10-like (zebrafish)
WAGR Syndrome
Wilms tumor 1
Wilson-Turner X-linked mental retardation syndrome
4q31.1
11q13.3
11q13.3
12q24.21
12q13.11
7q22
20p11.21
11p13
11p13
Xq21.2-q22
3p24.1
6p21.3
1p36.21
Xq13.1
11p15.5
U–Z
UCP1
UCP2
UCP3
UMS
VDR
VGF
VSX1
WAGRS
WT1
WTS
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