The Human Obesity Gene Map:
The 2002 Update
Yvon C. Chagnon,* Tuomo Rankinen,† Eric E. Snyder,† S. John Weisnagel,‡ Louis Pérusse,‡
and Claude Bouchard†
Abstract
CHAGNON, YVON C., TUOMO RANKINEN, ERIC E.
SNYDER, S. JOHN WEISNAGEL, LOUIS PÉRUSSE,
AND CLAUDE BOUCHARD. The human obesity gene
map: the 2002 update. Obes Res. 2003;11:313–367.
This is the ninth update of the human obesity gene map,
incorporating published results through October 2002
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 various
animal crossbreeding experiments, and association and
linkage studies with candidate genes and other markers is
reviewed. For the first time, transgenic and knockout
murine models exhibiting obesity as a phenotype are
incorporated (N ⫽ 38). As of October 2002, 33 Mendelian syndromes relevant to human obesity have been
mapped to a genomic region, and the causal genes or
strong candidates have been identified for 23 of these
syndromes. QTLs reported from animal models currently
number 168; there are 68 human QTLs for obesity phenotypes from genome-wide scans. Additionally, significant linkage peaks with candidate genes have been identified in targeted studies. Seven 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 222 studies reporting positive associations with 71 candidate genes.
Fifteen such candidate genes are supported by at least
Received for review December 16, 2002.
Accepted in final form December 17, 2002.
*Psychiatric Genetic Unit, Laval University Robert-Giffard Research Center, Québec,
Canada; †Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana
State University, Baton Rouge, Louisiana; and ‡Division of Kinesiology, Department of
Social and Preventive Medicine, Faculty of Medicine, Laval University, Sainte-Foy, Québec, Canada.
Address correspondence to Yvon C. Chagnon, Ph.D., Psychiatric Genetic Unit, Laval
University Robert-Giffard Research Center, 2601, chemin de la Canardière, room F-6459,
Beauport (Québec), G1J 2G3 Canada.
E-mail: [email protected]
Copyright © 2003 NAASO
five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. More than 300
genes, markers, and 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 review is
the ninth in a series (1– 8) on the status of the human
obesity gene map; this is the eighth report published in
Obesity Research. As in previous versions of the map, the
current publication incorporates material published up to
the end of October 2002. The review includes publications that have dealt with a variety of phenotypes pertaining to obesity; such phenotypes include body mass
index (BMI),1 body-fat mass, percentage of body fat,
fat-free mass, skinfolds, resting metabolic rates, plasma
leptin levels, and other components of 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 human mutations, Mendelian disorders exhibiting
1
Nonstandard abbreviations: BMI, body mass index; QTL, quantitative trait locus; Tg,
transgenic; KO, knockout; NCBI, National Center for Biotechnology Information;
OMIM, Online Mendelian Inheritance in Man; FPL, familial partial lipodystrophy;
FPLD, familial partial lipodystrophy, Dunnigan variety; PWS, Prader-Willi syndrome;
snoRNA, small nucleolar RNA; BBS, Bardet-Biedl syndrome; MGD, Mouse Genome
Database; Lod, linkage-odds; BMIf, female-only phenotype of BMI; BMIm, male-only
phenotype of BMI; PPCD, posterior polymorphous corneal dystrophy; CGC, composite
double-backcross cross.
OBESITY RESEARCH Vol. 11 No. 3 March 2003
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The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
a phenotype of relevance to human obesity, quantitative
trait loci (QTLs) 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 pictogram of the
2002 human obesity gene map. A novel section deals with
transgenic (Tg) and knockout (KO) mice, the phenotypes of
which include alterations in adiposity levels or 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 Web site (http://www.ncbi.nlm.nih.gov/LocusLink)
available from the National Center for Biotechnology Information (NCBI), which provides the official nomenclature of genetic loci.
From the numerous comments and feedback received
over the years, we gather that the reviews of the status of the
human obesity gene map have been helpful to the obesityresearch communities. We renew our request for comments
from those who are interested in any aspect of the gene map.
The electronic version of the human obesity gene map with
numerous useful links is available at http://obesitygene.
pbrc.edu.
Single-Gene Mutations
This last year has not witnessed any major advances in
human single-gene obesity syndromes. Among the
known causal genes (see Table 1), three new mutations
have been reported in the melanocortin-4 receptor gene
(MC4R). Kobayashi et al. (9) described a 40-year-old
Japanese woman with a BMI of 62 kg/m2. She carried a
G98R variant, which was found to severely impair ligand
binding and signaling in transfection studies. She had a
history of hyperphagia and no discernable endocrine deficit. In a study of several cohorts of white and black
subjects, Jacobson et al. (10) reported on two novel
deletions in the heterozygous state in white subjects. A
⫺65delTG mutation was found in one morbidly obese
(BMI ⬎40 kg/m2), 40-year-old woman. A second
171delC mutation in codon 57 was found in a 41-year-old
woman with hypertension, hyperinsulinemia, hypertriglyceridemia, and a BMI of 40 kg/m2. These variants
were not present in any other subject tested.
In another study, Lee et al. (11) reported on a 13-year-old
girl from Singapore. She had a BMI of 36.6 kg/m2, and her
father had a BMI of 32.7 kg/m2. Both carried a novel
heterozygous mutation Ile183Asn (T548A) in the melanocortin-3 receptor gene (MC3R). Although the proband’s
mother was also obese, she did not carry this variant. Also,
the daughter and father differed substantially in fat mass;
the proband had a body-fat percentage of 49%, whereas her
father had one of only 30%. Therefore, the significance of
the mutation in this gene remains to be determined.
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OBESITY RESEARCH Vol. 11 No. 3 March 2003
In rodent models (Table 2), the new gene Lpin1 that
lowers adipose-tissue mass when mutated has been cloned
by position from the fld mouse showing a phenotype of
lipodystrophy (12). Two mutations have been observed, fld
and fld2l; the first represents a severe chromosomal rearrangement, and the second represents a Gly84Arg substitution. These mutations result in an absent or nonfunctional
protein, respectively. Two Lpin-related mouse genes (Lpin2
and Lpin3), as well as the three human equivalents (LPIN1,
LPIN2, LPIN3) have been identified by sequence comparison in the databases. We have also added to these models
the OLETF rat, which is naturally mutated in the cholecystokinin receptor A (CCKAR) gene and results in mild
obesity (13,14). Similarly, the Little mouse showed a
growth hormone deficiency associated with decreased somatic growth but increased body fat despite normophagia
(15).
Mendelian Disorders
Progression in the discovery of causal genes for the
various adiposity-related Mendelian disorders described in
the Online Mendelian Inheritance in Man (OMIM) database
continues. Of the 37 syndromes with known map locations, 23
now have well-defined genes or strong candidates (Table 3).
Among the autosomal-dominant syndromes, several
groups have reported on mutations in the lamin A/C
(LMNA) gene in familial partial lipodystrophy (FPL), Dunnigan variety (FPLD). Shackleton et al. (16) described several families and individuals with FPLD, all of whom carried heterozygous mutations in exon 8 of LMNA, disrupting
both lamins A and C. The most frequent was an arginineto-tryptophan substitution in codon 482 (R482W; CGG to
TGG). Other mutations found were R482Q [already reported by Cao and Hegele (17)], R482L, K486N, and
K486N (two different nucleotide substitutions). Speckman
et al. (18) also reported the R482Q and R282W mutations as
the most frequent, as well as two others: a G465D alteration
in the same codon and a R582H mutation within exon 11,
which was found in a family with atypical FPLD. In a more
recent report, Garg et al. (19) compared women carrying
mutations in exon 8 (G465D, R482Q, and R482W) with
those having the R582H mutation within exon 11. This
latter group demonstrated atypical FPLD with a less-severe
phenotype. Finally, in a patient with a non-Dunnigan FPL,
Agarwal and Garg (20) described a heterozygous C-to-T
mutation at nucleotide 1273 in exon 6 in the peroxisome
proliferator-activated receptor-␥ gene (PPAR␥), located at
3p25. This R425C mutation was absent from unaffected
family members and normal subjects and was the probable
cause of the FPL.
In a family with posterior polymorphous corneal dystrophy (PPCD), a corneal endothelial dystrophy in which obesity has been observed, Biswas et al. (21) discovered a
Gln455Lys mutation in COL8A2, the gene encoding the ␣2
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 1. Cases of human obesity caused by single-gene mutations
Gene
Location
Mutation
LEPR
POMC
1p31
2p23.3
PCSK1
SIM1
LEP
5q15-q21
6q16.3-q21
7q31.3
MC4R
18q22
G 3 A (exon 16)
G7013T & C7133⌬ (exon 3)
C3804A (exon 2)
Gly483Arg A 3 C⫹4 (intron 5)
C1328 3 T (exon 9)
G398⌬ (codon 133)
C 3 T (codon 105) (exon 3)
CTCT631⌬ (codon 211)
GATT732ins (codon 246)
CIO5A Tyr35X
47insG
A31G
C52T
C449T
A508G
C493T
T749A
T902C
Ile137Thr
GTins279
Cdel28-bp
N66S
T112M
R165Q
C271Y
V253I
V103I
I251L
N274S
Val50Met
Ser58Cys
Ile102Ser
Ile170Val
G98R
⫺65delTG
171delC
Age (years)
BMI (kg/m2)
References
3
2
13 to 19
3 to 7
52.5 to 71.5
NA
(160)
(161)
1
1
2
4
10
5
11
1
1
1
1
1
1
1
1
1
3
1
5
1
1
2
1
5
7
2
2
2
1
2
1
1
1
3
6.6
2 to 8
6 to 34
4 to 81
11 to 58
8 to 64
28 to 52
NA
29.5
36.6 to 45.8
32.5 to 55.8
27.7 to 41
30 to 57
25.9 to 56.6
41.5 to 64.5
(162)
(163)
(164)
(165,166)
(167–169)
(170)
(167,169)
(171)
43
8.3 to 36
NA
5 to 21
NA
NA
7.9 to 40
NA
6.9 to 36
NA
52 to 55
6 to 39
12.5 to 39
16.2
13 to 45
40
40
41
57
SDS ⫽ 4.17
(172)
(173)
41.7 to 43
SDS ⫽ 2.8 to 5.4
SDS ⫽ 2.1 to 4.2
SDS ⫽ 4.1
SDS ⫽ 3.8 to 4.4
62
⬎40
40
(174)
(175)
N*
(9)
(10)
NA, not available; SDS, mean BMI SD score.
* Number of published cases.
chain of type VIII collagen, located at 1p34.3-p32. No
unaffected individuals carried the mutation. Hence, this
would be the second locus described for PPCD and the only
one for which a highly probable causal gene has been
identified.
Although many studies have focused on the Prader-Willi
syndrome (PWS), no clear novel gene has been reported
since last year’s review. However, Meguro et al. (22) demonstrated the possible role of a direct-repeat cluster of
multiple small nucleolar RNA (snoRNA) genes within the
OBESITY RESEARCH Vol. 11 No. 3 March 2003
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The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 2. Natural single-gene mutation in rodent models of obesity
Rodent
Mutations*
Diabetes (db)†
Fatty liver dystrophy (fld)
Fat (fat)
OLETF
Little
Obese (ob)
Tubby (tub)
Mahogany (mg)
Agouti yellow (Ay)
Human
Chr Genes Inheritance Chr
4
12
8
5
11
6
7
2
2
Lepr
Lpin1
Cpe
Cckar
Gh
Lep
Tub
Atrn
Ay
Recessive
Recessive
Recessive
Recessive
Recessive
Recessive
Recessive
Recessive
Dominant
1p31
2p21
4q32
4p15.2-p15.1
17q24.1
7q31.3
11p15.5
20p13
20q11.2-q12
Genes
Gene product
References
LEPR
LPIN1
CPE
CCKAR
GH
LEP
TUB
ATRN
ASIP
Leptin receptor
Lipin
Carboxypeptidase E
Cholecystokinin receptor A
Growth hormone
Leptin
Insulin signaling protein
Attractin
Agouti signaling protein
(176,177)
(12)
(178)
(13,14)
(15)
(179)
(180–182)
(183,184)
(185)
Status as of October 2002.
Chr, chromosome.
* The strain carrying the Adult (ad) dominant mutation on chromosome 7 is now extinct.
† Homologous to rat fat (fa)/corpulent (cp).
SNRPN-IPW critical PWS interval. A very recent study by
Gallagher et al. (23) confirmed this evidence, narrowing
down the minimal critical PWS region to a ⬃121-kb interval comprising the PWCR1/HBII-85 cluster of snoRNA
genes and the single HBII-438A snoRNA gene.
A Prader-Willi-like syndrome with deletions and duplication/deletions between 6q14 to 6q16 has been described
previously (24 –29). In a recent study, Faivre et al. (30)
reported on a child with the same phenotype harboring a
deletion of 6q16.2, exactly at the SIM1 gene, which has
already been implicated in a single-gene disorder (see Table
1). Thus, this category of Prader-Willi-like syndromes
might be caused by SIM1 gene deletions.
Finally, this year we add a syndrome omitted in previous
reviews, the WAGR syndrome (for Wilms tumor, aniridia,
genitourinary abnormalities, and mental retardation), where
severe obesity has been described by Marlin et al. (31),
Tiberio et al. (32), and Gul et al. (33). This syndrome is
caused by deletions at 11p14-p12. The causal gene is unknown.
In the autosomal recessive syndrome category, several
new genes have been identified. Alstrom syndrome is now
known to be caused by mutations in the ALMS1 gene,
comprising 23 exons over 224 kb of genomic DNA and
encoding a protein of 4169 amino acids. Six mutations (two
nonsense and four frameshift) causing premature stop
codons were described by Hearn et al. (34). Collin et al. (35)
also found six mutations (two nonsense and four frameshift,
including one found by Hearn).
Among the Bardet-Biedl syndromes (BBSs), BBS1, the
gene causing the corresponding syndrome, was identified
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by Mykytyn et al. (36). It is composed of 17 exons spanning
23 kb, and the authors found four mutations among six
families studied. Katsanis et al. (37) demonstrated that
mutations in BBS4 (or MYO9A), the gene causing the
corresponding syndrome, is a contributor to BBS in ⬍3% of
affected families. In the BBS6 gene (also designated
MKKS), Slavotinek et al. (38) reported on five new mutations (three in exon 3 and two in exon 4).
Agarwal et al. (39) identified the causal gene in congenital generalized lipodystrophy; the gene is also known as
Berardinelli-Seip congenital lipodystrophy 1 (BSCL1).
Eleven different mutations were found in this gene which
encodes 1-acylglycerol-3-phosphate O-acyltransferase 2, a
key intermediate enzyme in triacylglycerol and glycerolphospholipid biosynthesis.
In a recent systematic review of Cohen syndrome patients
by Kivitie-Kallio et al. (40), obesity, occurring in only 17%
of patients, was found to be a minor component of the
syndrome. Finally, in another recent review, Santer et al.
(41) described 33 different mutations (9 missense, 7 nonsense, 10 frameshift, and 7 splice-site) in the SLC2A2 gene
at the origin of the Fanconi-Bickel syndrome.
As for the X-linked syndromes, the candidate gene for
Borjeson-Forssman-Lehmann syndrome (BFLS) was discovered by Lower et al. (42). A zinc-finger gene, plant
homeodomain-like finger 6 (PHF6), had eight different
missense and truncation mutations in seven familial and
two sporadic cases of Borjeson-Forssman-Lehmann syndrome. PHF6 is an 11-exon gene encoding a 365-aminoacid protein of unknown function. In addition, Leshinski-
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 3. Obesity-related Mendelian disorders with known map location*
OMIM
no.
Syndrome
Locus
Candidate gene Reference
Autosomal dominant
100800
103580
300800
103581
105830
605746
151660
604517
147670
122000
176270
Achondroplasia (ACH)
Albright hereditary osteodystrophy (AHO)
4p16.3
PHF6, FGF13
20q13.2-q13.3 GNAS1
(186–189)
(190–203)
Albright hereditary osteodystrophy 2 (AHO2)
Angelman syndrome with obesity (AGS)
Anisomastia
Familial partial lipodystrophy Dunnigan (FPLD)
FPL (non-Dunnigan)
Insulin resistance syndromes (IRS)
Posterior polymorphous corneal dystrophy (PPCD)
Prader-Willi syndrome (PWS)
15q
15q11-q13
16q13
1q21.2-q21.3
3p25
19p13.3-p13.2
20q11
15q11-q13
(204)
(205)
(206)
(16–19,207,208)
(20)
(209–216)
(21,217)
(22–24,26,27,29,218–229)
Prader-Willi-like syndrome
190160 Thyroid hormone resistance syndrome (THRS)
181450 Ulnar-mammary syndrome schinzel syndrome (UMS)
154072 WAGR syndrome
6q16.2-q14
3p24.3
12q24.1
11p13
NA
NA
NA
LMNA
PPARG
INSR
COL8A2
IPW
SNRPN
NDN
ZNF127
MAGEL2
PWCR1
SIM1
THRB
TBX3
NA
(24–30)
(230)
(231)
(31–33)
Autosomal recessive
203800
209901
209900
600151
600374
603650
209900
604896
269700
606158
212065
216550
601538
227810
139191
Alstrom syndrome (ALMS1)
Bardet-Biedl syndrome 1 (BBS1)
Bardet-Biedl syndrome 2 (BBS2)
Bardet-Biedl syndrome 3 (BBS3)
Bardet-Biedl syndrome 4 (BBS4)
Bardet-Biedl syndrome 5 (BBS5)
Bardet-Biedl syndrome 6 (BBS6)
2p13-p12
11q13
16q21
3p13-p12
15q22.3-q23
2q31
20p12
ALMS1
BBS1
BBS2
NA
BBS4 (MYO9A)
NA
MKKS
(34,35,232,233)
(36,234–236)
(234,237,238)
(239–241)
(37,234,242–244)
(245,246)
(38,247,248)
Berardinelli-Seip congenital lipodystrophy (BSCL1)
Berardinelli-Seip congenital lipodystrophy (BSCL2)
Carbohydrate-deficient glycoprotein type 1a (CDGS1A)
Cohen syndrome (COH1)
Combined pituitary hormone deficiency (CPHD)
Fanconi-Bickel syndrome (FBS)
Isolated growth hormone deficiency (IGHD)
9q34
11q13
16p13.3-p13.2
8q22-q23
5q
3q26.1-q26.2
7p15-p14
AGPAT2
BSCL2
PMM2
NA
PROP1
SLC2A2
GHRHR
(39,249)
(250)
(251–253)
(254,255)
(256,257)
(41,258–261)
(262,263)
X-linked
301900 Borjeson-Forssman-Lehmann syndrome (BFLS)
303110 Choroideremia with deafness (CHOD)
300148 Mehmo syndrome (MEHMO)
Xq26.3
PHF6, FgF13
Xq21.1-q21.2 NA
Xp22.13-p21.1 NA
(42,264,265)
(266,267)
(43,268,269)
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The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 3 (continued)
OMIM
no.
Syndrome
300218
176270
300238
312870
Mental retardation X-linked, syndromic 7 (MRXS7)
Prader-Willi-like syndrome
Mental retardation, X-linked, syndromic 11 (MRXS11)
Simpson-Golabi-Behmel 1 (SGBS1)
Simpson-Golabi-Behmel 2 (SGBS2)
309585 Wilson-Turner syndrome (WTS)
Locus
Candidate gene Reference
Xp11.3-q22.1
Xq23-q25
Xq26-q27
Xq26.1
Xp22
Xp21.2-q22
NA
NA
NA
GPC3, GPC4
NA
NA
(270)
(271)
(272)
(273–280)
(281)
(282,283)
Status as of October 2002.
NA, not available.
* Adapted from OMIM (Online Mendelian Inheritance in Man) computerized database.
-Silver et al. (43) identified MEHMO (for mental retardation, epileptic seizures, hypogenitalism, microcephaly,
obesity) as a mitochondrial disorder. No new causal
genes for this or the remaining X-linked syndromes have
been identified.
KO and Tg Models
This year we reviewed KO and Tg experiments that
evidenced changes in obesity-related phenotypes. Our review focuses only on genes that are new candidates for
obesity and on those for which a human equivalent can be
found. Some 39 KO or Tg models are presented with a brief
description of the effects (Table 4). This new section will be
expanded considerably in subsequent versions of the map.
QTLs from Crossbreeding Experiments
Relatively few new studies have been reported in the last
year on QTLs related to obesity (Table 5). In mice, a study
from a SM/J ⫻ A/J cross reported two new QTLs on
chromosomes 8 (Bwq3) and 18 (Bwq4), respectively, explaining each 6% of the variance in body weight (44). In rat,
a QTL (Imfq1) from an OLETF ⫻ F344 cross explained 5%
of the intramuscular-fat content (45). In pig, the SSC7 QTL
for back-fat thickness on chromosome 7 has been confirmed
again in a Meishan ⫻ Göttingen cross (46). Finally, in
cattle, a significant QTL on chromosome 17 (named
BTA17LW) that lowered live weight by 24 kg was reported
in a Hereford ⫻ composite double-backcross cross (CGC)
(47). On the other hand, suggestive or negative results have
also been reported, but are not included in the present
review. Moreover, we have now decided to remove the
QTLs based on chicken models because the synteny with
the human genome cannot be established (48,49).
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OBESITY RESEARCH Vol. 11 No. 3 March 2003
Three studies reported suggestive QTLs with body
weight (50 –52), whereas others reported either no effect
(53) or effects on the weight of only organs (54,55). In pig,
a QTL for muscle glycogen that seemed to be modulated by
alleles at the protein kinase adenosine monophosphate-activated ␥3-subunit (PRKAG3) gene has been uncovered
(56), but no QTL for body weight or back-fat has been
found (57). In cattle, a haplotype associated with birth
weight was reported on chromosome 5 (58). Hence, with
168 animal QTLs being reported, the number of animal
QTLs linked to body weight or body fat has increased by
only four since the last review (Table 5). The equivalent
syntenic regions in humans, when they can be determined
from available maps, are shown in Table 5. We have proposed acronyms for QTLs to facilitate their inclusion in the
map when none was provided by the authors or by the
Mouse Genome Database (MGD) (59). Because new maps
are now available from the MGD, we have updated the
cytological location of the mouse QTLs showing multiple
locations from the MGD or by the location of the QTL
estimated in the MGD from linked markers and the synteny
provided by the NCBI mouse– human map (60). No update
was made for other species. For the rat, maps described in
Yamada et al. (61) and Jacob et al. (62) were used. For the
pig QTLs, maps from the Animal Genome Database in
Japan (63) and from the U.S. Livestock Genome Mapping
Projects (64) were used.
Association Studies
The evidence for associations between candidate genes
and obesity-related phenotypes is summarized in Table 6.
Two hundred twenty-two studies covering 71 candidate
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 4. Selected knockout (KO) and transgenic (Tg) rodent models of obesity
Rodent
Human
Chr
Gene
Mutations
Chr
Gene
Product
3
NA
1
Nhlh2
Pkar2b
Hsd11b1
KO; obesity (maturity onset)
KO; ⬍FATw; ⬎MR
Tg; obesity
1p12-p11
1q12
1q32-q41
NHLH2
PRKAB2
HSD11B1
13
12
17
2
6
3
NP
13
5
8
Chrm3
Sdc1
Fshr
Il1rn (Il-1ra)
H1r
GabtI
NP
Drd1a
Vgf
Eif4ebp1
KO; ⬍BW
Tg; obesity (maturity onset)
KO; obesity
KO; ⬍BW
KO; ⫹⌬BW (high fat diet)
Tg; obesity
Tg; ⬎FAT
KO; ⬍BW
KO; ⬍BW; ⬍FAT; ⬎MR
KO; ⬍FATw; ⬎MR
1q41-q44
2p24.1
2p21-p16
2q14.2
3p25
3p25-p24
4p16.3
5q34-q35
7q22
8p12
CHRM3
SDC1
FSH-R
IL1RN
HRH1
SLC6A1
HD
DRD1
VGF
EIF4EBP1
6
15
Fabp4 (aP2)
Dgat
KO; ⬎⫹⌬FAT (high-fat diet)
KO; ⬎FAT/NW (high-fat diet)
8q21
8q-ter
FABP4
DGAT1
15
10
5
10
Gdc1
Hmga2
Ptprb
Pmch
12q13.2
12q15
12q15-q21
12q23-q24
GPD1
HMGA2
PTPRB
PMCH
5
12
9
7
8
Acc2
Batf (A-ZIP/F)
Cyp19
Plin
Mt
Tg; ⫺FATw
KO; resistant to high-fat diet
KO; resistant to high-fat diet
KO; ⬍BW; ⬍FI
Tg; obesity
KO; ⬍FAT; ⬎FI
Tg; ⫺FAT; ⬎BWf
KO; ⬎AF
KO; ⬍FM; ⬎FFM; ⬍MR
KO; obesity; ⬎FATw (epididymal)
Neural transcription factor 2
Protein kinase A RII␤
Hydroxysteroid (11-beta)
dehydrogenase 1
Muscarinic receptor M3
Syndecan 1
Follicular stimulating hormone receptor
Interleukin 1 receptor antagonist
Histamine receptor H1
Gamma-aminobutyric acid transporter I
Huntingtin
Dopamine receptor D1
Neural expressed protein
Eukaryotic translation initiation factor
4E binding protein 1
Fatty acid binding protein 4
Acyl CoA: diacylglycerol acyl
transferase
␣-Glycerol phosphate dehydrogenase
Component enhancesome Hmgic
Protein tyrosine phosphatase 1 B
Melanin concentrating hormone
12q24.1
14q24.3
15q21
15q26
16q13
8
Srebf1/2
Tg; lipodystrophy
17p11.2
ACACB
BATF
CYP19
PLIN
MT1A
MT1B
SREBP-1C/1A
11
Stat5
17q11.2
STAT5A
11
11
17
9
7
7
7
2
7
2
Hcrt
Ppy
C3
Icam1
Cebp
Tgfb1
ApoC1
Ghrh
Cebp
Ptpn1
KO; ⬍BW; ⬍FAT (young);
obesity
KO; obesity (late onset)
Tg; ⬍BW; ⬍FI; ⬍FAT
KO; ⬍FAT; ⬍BWf
KO; obesity (late onset)
KO; ⬍FATw; ⫺FATb
Tg; ⬍BW; ⬍FAT
Tg; ⬍BW; ⬍FAT
Tg; ⬎%AF
KO; ⬍FATw; ⫺FATb
KO; Obesity (resistant)
17q21
17q21
19p13.3
19p13.2
19q13.11
19q13.1
19q13.2
20q11.2
20q12-q13.1
20q13.1-q13.2
HCRT
PPY
C3
ICAM-1
CEBPA
TGFB1
APOC1
GHRH
CEBPB
PTPN1
X
Brs3
KO; ⬎FAT; ⬍EE
Xq26-q28
BRS3
Acetyl CoA Carboxylase 2
Regulator of transcription factor B-ZIP
Transferase aromatase
Perilipin
Metallothionein I & II
Sterol regulatory element binding
protein
Signal transducer and activator of
transcription 5
Hypocretin (Orexin)
Pancreatic polypeptide
Acylation-stimulating protein
Intercellular adhesion molecule 1
CCAAT enhancer binding protein
Transforming growth factor, beta 1
Apolipoprotein C1
Growth hormone releasing hormone
CCAAT enhancer binding protein
Protein tyrosine phosphatase, nonreceptor type 1
Bombesin receptor 3
References
(284)
(285)
(286)
(287)
(288)
(289)
(290)
(291)
(292)
(293)
(294)
(295)
(296)
(297)
(298)
(299)
(300)
(301)
(302)
(303)
(304)
(305)
(306)
(307,308)
(309)
(310,311)
(312)
(313)
(314)
(315)
(316)
(317)
(318)
(319)
(320)
(321)
(301)
(322)
Adapted from (323,324) and original papers.
Status as of October 2002.
⫺FAT, no fat; AF, abdominal fat; NW, normal weight; MR, metabolic rate; FI, food intake; EE, energy expenditure; NA, not available; NP, not applicable;
BW, body weight; ⫹⌬, gain; FFM, fat-free mass; subscript w, white; subscript f, female; subscript b, brown; FM, fat mass.
OBESITY RESEARCH Vol. 11 No. 3 March 2003
319
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 5. QTLs reported for animal polygenic models of obesity with their putative syntenic locations in the
human genome*
Chromosomes
Crosses
Mouse
M. spretus ⫻ C57BL/6J
Mouse
Mouse
NZB/B1NJ ⫻ SM/J
CAST/Ei ⫻ C57BL/6J
Mouse
AKR/J ⫻ SWR/J
Mouse
Mouse
NZO ⫻ SJL
NZO/H1Lt ⫻ NON/Lt
Mouse
A/J ⫻ M. spretus ⫻
C57BL/6J
Mouse
JU/CBA ⫻ CFLP (P6)
Mouse
Du6 ⫻ DuK
Mouse
Du6 ⫻ Duk
Mouse
Du6i ⫻ DBA/2
Mouse
129/Sv ⫻ Le/Suz
Mouse
AKR/J ⫻ C57L/J
Mouse
NZO ⫻ SM
320
QTL
Statistics
Phenotypes
Animal
Human
References
Mob1
Mob2
Mob3
Mob4
Mob5†
Mob6
Mob7
Mob8
Qlep
Bl/Bw
Dob1
Dob2
Dob3‡
Nob1
Nzoq1
Lod ⫽ 4.2
Lod ⫽ 4.8
Lod ⫽ 4.8
Lod ⫽ 3.4
Lod ⫽ 3.6
Lod ⫽ 7.3
Lod ⫽ 5.7
Lod ⫽ 4.7
Lod ⫽ 5.2
Lod ⫽ 4.3/2.5
Lod ⫽ 4.5
Lod ⫽ 4.8
Lod ⫽ 3.9
Lod ⫽ 3.8
Lod ⫽ 3.8 to 9.4
6.5% percent fat
7.1% femoral fat
7.0% percent fat
5.9% mesenteric fat
36% body fat
Subcutaneous fat
Subcutaneous fat
Body fat (%)
Leptin level (no obesity)
Body length/body weight
NA
7% adiposity
4% adiposity
16.8% BMI
16% body weight
7
6
12
15
2
2
2
9
4
15
4
9
15
5
1
(325)
Lod ⫽ 3.3/4.0
Lod ⫽ 3.4
Lod ⫽ 6.6
Lod ⫽ 4.3
Lod ⫽ 24.4
Leptin/BMI
24% body weight
(three QTLs together)
17% to 20% 10-week weight
12
X
X
X
X
16p12.1-p11.2
7q31.2-q31.3
14q32.1-q32
5p14-p13
20q13.1-q13.3
11p11.2
3p21.3
6p12.1
9p22
8q22-q23
1p33-p32
3p21
8q24.1
4p15
6p12-p11
2q11.2-q35
14q31-q32
Xp11-q26
Xq11-q13
Xp22-q27
Xq28
Nzoq2
Bw1§
Bw2§
Bw3
Bw19
(QbwX)
Qbw1
Qbw2
Bw4
Afw1/Afp1
Afw2
Afw3
Afp2
Bw5
Bw13
Afpq9/Afw9
Bw14
Bw16
Afpq10/Afw10
Bw15
Lepq1
Afpq6
Obq1
Obq2
Obq3
Obq4
Obq4
Obq7
Obq8
Obq9
Obq10
Obq11
Obq12
Lod ⫽ 2.7
Lod ⫽ 7.6
F ⫽ 4.79
F ⫽ 4.89
F ⫽ 4.79
F ⫽ 4.70
F ⫽ 4.89
F ⫽ 10.4
F ⫽ 11.7
F ⫽ 18.5/24.9
F ⫽ 25.9
F ⫽ 7.52
F ⫽ 7.48/8.56
F ⫽ 7.36
F ⫽ 7.58
F ⫽ 8.92
Lod ⫽ 8.0
Lod ⫽ 5.5
Lod ⫽ 5.1
Lod ⫽ 4.6
Lod ⫽ 6.3
Lod ⫽ 6.5/6.0
Lod ⫽ 6.4
Lod ⫽ 6.7
Lod ⫽ 6.4
Lod ⫽ 4.4/4.1
Lod ⫽ 5.3/4.5
6.9% abdominal fat
17% body mass
23.1% body weight
10% to 13% abdominal fat
8.3% abdominal fat
7.7% abdominal fat
8.3% abdominal fat (%)
5.4% body weight
6.0% body weight
9.1/12.0% abdominal fat (%)
12.3% body weight
3.9% body weight
3.9/4.5% abdominal fat (%)
3.8% body weight
4.4% leptin
4.6% abdominal fat (%)
12.3% adiposity
6.3% adiposity
7.0% adiposity
6.1% adiposity
Inguinal fat % (males)
Gonadal/mesenteric fat % (males)
Retroperitoneal fat %
Mesenteric fat % (females)
Gonadal fat % (males)
Mesenteric fat/gonadal %
Mesenteric fat/gonadal %
3
11
11
4
11
13
3
1
5
7
7
11
12
13
14
17
7
1
2
17
17
1
1
1
2
5
5
4q23-q27
17q12-q22
17q21-q22
1p34-p33
7p13-p11.2
1q43
3q25
2q34
7p22
19q13.3
15q11-12
2p13.3
7p15
7p14-p13
8p21-p12
19p13.3-p13.2
19q13.2-q13.3
6q12-q14
11p11.2
6q27
6q27
2q33.1
1q31
1q22-q23
11p13
7q22-q36
4p15
OBESITY RESEARCH Vol. 11 No. 3 March 2003
(326)
(327)
(328)
(329)
(330)
(331)
(332)
(333)
(334)
(335)
(336)
(337)
(338)
(339)
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 5 (continued)
Chromosomes
Crosses
Mouse
TSOD ⫻ BALB/cA
Mouse
CAST/Ei ⫻ M16i
Mouse
KK/H1Lt ⫻ C57BL/6J
Mouse
KK-A(y) ⫻ C57BL/6J
Mouse
CAST/EiJ ⫻ C57BL/
6J-hg/hg
MH ⫻ C57BL/6J
Mouse
Mouse
DBA/2J ⫻ C57BL/6J
Mouse
DBA/2J ⫻ C57BL/6J
Mouse
Wild M. m. castaneus ⫻
C57BL/6J
QTL
Statistics
Phenotypes
Obq13
Obq14
Obq15
Nidd5
Nidd6
Pfat1
Lod ⫽ 5.1 to 6.0/9.3
Lod ⫽ 3.9 to 4.1/9.2
Lod ⫽ 6.6
Lod ⫽ 5.91
Lod ⫽ 4.65
NA
3 pads/mesenteric fat %
3 pads/mesenteric fat %
Gonadal fat % (males)
10.9% body weight
9.2% body weight
Adiposity
6
6
7
2
1
2
Pfat2
NA
Adiposity
2
Pfat3
Pfat4
NA
NA
Adiposity
Adiposity
13
15
Pfat5
Pfat6
NA
NA
Adiposity
Adiposity
15
17
Obq5
Obq6
KK7
Bwq1
Bwq2
Carfhg1
Carfhg2
Hlq1
Hlq2
Lod ⫽ 6.3
Lod ⫽ 5.0
Lod ⫽ 6.9/4.4
Lod ⫽ 3.1
Lod ⫽ 3.4/4.1
Lod ⫽ 2.5
Lod ⫽ 5.8
Lod ⫽ 5.6
Lod ⫽ 3.7
17% adiposity (females)
11.7% adiposity (males)
Body weight/inguinal fat
15% body weight
19% body weight/26% adiposity
6.2% fat content
12.5% fat content
4.7% heat loss
3.1% heat loss
9
X
7
4
6
5
9
1
2
Hlq3
Hlq4
Hlq5
Fatq1
Batq1
Batq2
Bw6a
Bw6b
Bw6c
Bw6d
Bw6e
Bw6f
Bw6g
Bw6h
Bw6i
Bw6j
Bw6k
Pfatp4
Pfatp6
Pfatp13
Pfatp15
C10bw1
C10bw2
C10bw3
C10bw4
C10bw5
Lod ⫽ 3.8
Lod ⫽ 4.7
Lod ⫽ 4.06
Lod ⫽ 8.0
Lod ⫽ 4.0
Lod ⫽ 3.5
Lod ⫽ 3.3
Lod ⫽ 3.3
Lod ⫽ 3.2
Lod ⫽ 4.3
Lod ⫽ 4.0
Lod ⫽ 6.9
Lod ⫽ 4.4
Lod ⫽ 5.7
Lod ⫽ 4.1
Lod ⫽ 3.0
Lod ⫽ 4.9
Lod ⫽ 5.0
Lod ⫽ 4.9
Lod ⫽ 5.3
Lod ⫽ 8.6
Lod ⫽ 10.7
Lod ⫽ 3.3
Lod ⫽ 3.7
Lod ⫽ 3.7
Lod ⫽ 3.4
3.1% heat loss
3.9% heat loss
3.4% heat loss
5.9% gonadal fat
3.3% brown fat
2.8% brown fat
3% 6-week weight
4% 6-week weight
4% 6-week weight
5% 6-week weight
4% 6-week weight
9% 6-week weight
5% 6-week weight
6% 6-week weight
4% 6-week weight
3% 6-week weight
7% 6-week weight
20% predicted fat (%)
(four QTLs together)
3
3
7
1
1
3
1
4
5
5
6
7
9
11
13
14
17
4
6
13
15
2
9
11
13
13
1.4
1.1
1.3
0.9
0.8
g
g
g
g
g
body
body
body
body
body
weight
weigh (females)
weight (males)
weight (females)
weight (males)
Animal
Human
7p14
3p26
11p15.5
2q22-q23
1q25
2q11-q14
15q21.1
20q13.11q13.13
5q23-q31
8q22-q23
5p15.2
8q24
16p13.3
19q13.4
11q23-q24
Xq26-q28
11q21
6q16
3p26-p25
4p15.1
11q25
1q21-q41
2p13-q13
15q21-q22
3q25
8q21.3-q22.1
16p12-p11.2
18q21.3
1q41-q42.1
4q28-q31
1q31-q33
9p24-p23
4q12-q13
12q24
2p12
19q13.3
6q12-q16
17p13
15q23-q25
8p23.1-p22
6p21
9p24
3p14.1-p12
5q22-q31
8q24-qter
2q24.2
15q21-q22
17q24-q25
5q13
5q14.3
References
(340)
(341)
(342)
(343)
(344)
(345)
(346)
(347)
(348)
OBESITY RESEARCH Vol. 11 No. 3 March 2003
321
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 5 (continued)
Chromosomes
Crosses
QTL
Statistics
Phenotypes
Mouse
C10bw6
C10bw7
Qsbw
Lod ⫽ 4.3
p ⫽ 0.00001
p ⬍ 0.009
1.4 g body weight (females)
Body weight (males; epistatic)
40% body weight
Q1w1/Skl1
Qlw2/Skl2
Qlw3
Qlw4/Wt1
Qlw5/
Adip2/Wt2
Qlw7/
Adip3
Qlw9/Adip5
Qlw10/Sk14
Qlw11
Qlw12
Qlw13/Adip7
Qlw14/Wt3
Qlw18/Adip8
Bwq3
Bwq4
Nidd3n
Fob1
Fob2
Lod ⫽ 2.3
Lod ⫽ 2.9
Lod ⫽ 2.3
Lod ⫽ 2.4¶/2.4
Lod ⫽ 2.8¶
Lod ⫽ 3.6/6.2 to 3.5
Lod ⫽ 2.0¶
Lod ⫽ 3.7/9.7
Lod ⫽ 2.5¶/1.8
Lod ⫽ 2.3¶/4.9
Lod ⫽ 2.6
Lod ⫽ 2.3
Lod ⫽ 2.4/1.9
Lod ⫽ 3.1/2.1
Lod ⫽ 1.6/2.8
Lod ⫽ 4.6
Lod ⫽ 4.8
Lod ⫽ 6.8
Lod ⬎ 3.3
Lod ⬎ 3.3
1.9% late weight gain
2.6% late weight gain
8.4% late weight gain
2.4% late weight gain/weight
3.4% late weight gain
Adiposity/weight (females)
2.0% late weight gain
Adiposity (males)/weight
2.4% late weight gain/adiposity
1.9% late weight gain/weight
2.4% late weight gain
2.4% late weight gain
4.4% late weight gain/adiposity
2.9% late weight gain/weight
3.0% late weight gain/adiposity
6% body weight at 10 weeks
6% body weight at 10 weeks
Epididymal fat
4.9% 14-weeks percentage of fat
19.5% 14-weeks %fat (female)
Lod ⫽ 11.3
Lod ⬎ 3.3
Lod ⫽ 2.3
Lod ⫽ 2.5
Lod ⫽ 2.2
14.4% 14-weeks %fat
7.3% 14-weeks %fat
5.4% weight (male)
5.8% BMI (male)
6.9% BMI (female)
15
X
1
Lod ⫽ 2.7
Lod ⫽ 3.0
NA
NA
NA
NA
7.8% weight (female)
8.3% BMI (female)
13% adiposity
9% body weight
7% body weight
24% body weight
12
1
8
17
7
Lod ⫽ 3.2
Lod ⫽ 3.0
Lod ⫽ 6.2
Lod ⫽ 6.0
Lod ⫽ 8.2 to 14.0
Lod ⫽ 4.4 to 5.5
Lod ⫽ 3.5 to 3.6
Lod ⫽ 3.5 to 3.6
Lod ⫽ 4.9 to 5.4
Lod ⫽ 3.5
23.5% body weight
NA
NA
11.6% body weight
Adipose index, fat and body weight
Fat weight, adipose index
Fat weight, adipose index
Fat weight, adipose index
Fat weight, adipose index
Adipose index
1
10
7
1
1
1
3
6
7
11
Mouse
Quackenbush-Swiss ⫻
C57BL/6J
SM/J ⫻ LG/J
Mouse
SM/J ⫻ A/J
Mouse
Mouse
NSY ⫻ C3H/He
F⫻L
Rat
Fob3
Fob4
Leprfa/Leprfa 13M ⫻ WKY Qfa1
Qfa12
Rat
GK ⫻ BN
Rat
GK ⫻ F344
Rat
Rat
322
Nidd/gk1
Nidd/gk5
Nidd/gk6
bw/gk1
Niddm1
Niddm3
Weight1
OLETF ⫻ BN
Dmo1
(OLETF ⫻ BN) ⫻ OLETF Dmo1
Dmo4
Dmo5
Dmo6p
Dmo7p
Dmo9
OBESITY RESEARCH Vol. 11 No. 3 March 2003
Animal
Human
X
12
10
Xp22.2-p21.2
14q23-q24.2
12q22-q23
1
2
3
4
6
2q35-q36
15q11.2-q22.2
3q25-q26
9q31-q32
3p26-p24
7
11p15
9
10
11
12
13
14
18
8
18
6
2
12
6p12.1
12q21
22q12
2p24-p23
1q43
14q11.2
5q31
16q22-q23
5q32-q35
2p14-p12
2q21-q37
7p22-q22
14q12-q13
8q24.2-q24.3
Xq12-q21.2
16q13
16p11
11p15
11q13
7q22
3p21
11q22-q23
1q41-q44
8q21-q24
22q12-q13
10q24-q26
17pter-q23
12q22-q23
10q23-q24
10q23-q24
11p15.5-p15.4
19p13.2-q13.3
14q32
12q22-q23
3q26.1-q28
References
(349)
(350–352)
(44)
(353)
(354)
(355)
(356)
(357)
(358)
(359)
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 5 (continued)
Chromosomes
Crosses
QTL
Statistics
Phenotypes
Dmo10
Lod ⫽ 3.5 to 3.6
Fat weight, body weight
OLETF ⫻ F344
Obs1
Lod ⫽ 5.1
13.8% mesenteric fat
Rat
OLETF ⫻ F344
Obs2
Obs3
Obs4
Obs5
Obs6
Imfq1
Lod ⫽ 4.2
Lod ⫽ 5.9
Lod ⫽ 5.3
Lod ⫽ 5.4
Lod ⫽ 4.5
Lod ⫽ 3.4
11.3% retroperitoneal
13.4% mesenteric fat
16.5% retroperitoneal
12.4% retroperitoneal
13.8% retroperitoneal
5% intramuscular fat
Rat
Rat
Dahl ⫻ MNS
SHR ⫻ BB/OK
Rat
Rat
SHR ⫻ Wild
WOKW ⫻ DA/K
DAHL3
SHR1
SHR4
SHR10
Wokw1/Q1ms1
p ⬍ 0.00003
Lod ⫽ 3.3
Lod ⫽ 3.1
Lod ⫽ 3.5
Lod ⫽ 4.9
13% body weight
32% body weight (males)
14% body weight (females)
Body weight (males)
31% 30-week body weight
3
1
4
10
1
Pig
European wild boar ⫻
Large White
16% BMI
NA
Back/abdominal fat
15.4% visceral fat
7.3% subcutaneous fat
9.7% body fat (%)
Back-fat thickness/depth
10.4% back-fat depth
Midback-fat depth
4% to 6% back-fat thickness
3% to 4% back-fat thickness
5
4
Rat
Pig
Pig
Pig
Iberian ⫻ Landrace
Wild Boar ⫻ Large White
Meishan ⫻ Large White
Meishan ⫻ White
Pig
Meishan ⫻ White
Pig
Meishan ⫻ Duroc,
Hampshire, Landrace
Minghu ⫻ Hampshire,
Landrace
Meishan ⫻ (Dutch
Landrace ⫻ Large White)
Pig
Pig
Meishan ⫻ Dutch
Wokw1/Q1ms5 Lod ⫽ 4.5
FAT1
NA
F ⫽ 15.8/18.6
p ⬍ 0.0001
p ⬍ 0.0001
p ⬍ 0.0001
F ⫽ 15.9/11.1
IGF2q
F ⫽ 7.1
BFM4
NA
SSC1:167–175 F ⫽ 12.6 to 43.2
SSC4:49–84
F ⫽ 14.9 to 15.3
Animal
11
2
fat
fat
fat
fat
4
8
9
14
14
1
21q22.1
22q11.2
5p13-p12
5q11.2-q13
7q11.2-q36
6q12-q13
6p21
4q12-q13
7p13-p12
9q12
10q23-q25.3
10q25
11p15.5
7p15.3
17pter-q23
3p21
10q24-q26
1p36-p31
1q21-q25
2% to 5% back-fat thickness
1% to 2% back-fat thickness
5% to 14% back-fat thickness
1% to 2% back-fat thickness
8% to 40% back-fat thickness
(males)
Weight; back-fat depth
Back-fat depth
Back-fat depth
Average back-fat
5
6
7
8
X
11p15.5
1q21-q25
15q25
1p13
1q22-q25
8q22
12p12
16q22-q24
6p12
4p16-p13
X
1
7
X
7
15q21
6p12
X
6p21
42-day weight
13
3p11
SSC5:35–42
SSC6:37–81
SSC7:51–72
SSC8:21–57
SSCX:65–85
F ⫽ 13.4 to 15.1
F ⫽ 11.9
F ⫽ 29.9 to 87.5
F ⫽ 9.5
F ⫽ 27.8 to 45.3
SSC1:136–138
SSC7:55–58
SSCX:76–79
Pig QTL2
PIT1
F ⫽ 39.8 to 94.9
F ⫽ 10.4 to 20.5
F ⫽ 37.4 to 71.8
p ⬍ 0.01,
F ⫽ 7.9
F ⫽ 3.34
SSC2
SSC7
F ⫽ 2.7¶
F ⫽ 18.0¶
Back-fat thickness
Back-fat thickness
SSC2
SSC6p
SSC6q
F ⫽ 24.1
F ⫽ 14.5
F ⫽ 14.7
Back-fat thickness (p)
Intramuscular fat (m)
Intramuscular fat (p)
2p
4
1
4
Human
2
7
2
6p
6q
11p15
6p21.3
15q22-qter
11p15
16q22-qter
1p33-p32
1p22
18p11.2
References
(360)
(45)
(361)
(362)
(363)
(364,365)
(366)
(367)
(368)
(369)
(370,371)
(372)
(373)
(374)
(375,376)
(377)
(378)
(379)
(380)
OBESITY RESEARCH Vol. 11 No. 3 March 2003
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The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 5 (continued)
Chromosomes
Crosses
Pig
Meishan ⫻ Dutch
Pig
Pig
Meishan ⫻ Göttingen
Meishan ⫻ White
composite
Pig
Berkshire ⫻ Yorkshire
Bovine
Hereford ⫻ CGC
QTL
Statistics
Phenotypes
Animal
Human
SSC7
SSCX
Back-fat thickness (p/m)
1.0% to 1.5% back-fat thickness
0.1 to 0.02% intramuscular fat
18% back-fat thickness
Back-fat thickness
Back-fat thickness
Back-fat thickness
4.8% back-fat
6.0% weight
4.8% back-fat
7
X
6p22-p21.3
Xq11.2-q22
SSC7
SSC1
SSC7
SSCX
SSC1:29
SSC4:123
SSC5:113
F ⫽ 30.3/49.4
F ⫽ 22.6
F ⫽ 12.8
F ⫽ 19.5
F ⫽ 15.4
F ⫽ 14.7
F ⫽ 32.3
F ⫽ 11.3
F ⫽ 11.8
F ⫽ 9.5
7
1
7
X
1
4
5
SSC7:58–72
BTA17LW
F ⫽ 11.1/13.8
F⫽8
5.3/6.9% back-fat
⫺24 kg live weight
7
17
6p21.3
9q32-q34.1
6p21.3
X
7q21-q24
1q12
15p13
15q22-q23
6p22-p21.1
4
References
(381)
(46)
(382)
(383)
(47)
Status as of October 2002.
Mob, multigenic obesity; Dob, dietary obese; Afw, abdominal fat weight; Afp, abdominal fat percent; Bl, body length; Bw, body weight; Obq, obesity QTL;
Pfat, polygenic fatness; Qlw, QTL late weight gain (6 to 10 weeks); Qbw, QTL body weight; Qlep, QTL for leptin; Bw6, body weight at 6 weeks; Qfa, QTL
LEPRfa; Nidd/gk, non-insulin dependent diabetes/Goto-Kakizaki; bw/gk, body weight/Goto-Kakizaki; Niddm, non-insulin dependent diabetes mellitus; Hlq,
heat loss QTL; Fatq, fat QTL; Batq, brown adipose-tissue QTL; Pfatp, predicted fat percent; Dmo, diabetic mouse; Fob, fat obesity; Wokw, Wistar Ottawa
Karlsburg Rt1uW; SHR, salt hypertensive rat; SSC, swine chromosome; C10bw, castaneus 10-week body weight QTL; Carfhg1 (Q5Ucd1-fp), carcass fat in
high growth mice 1; Nidd3n (Nidd3nsy), non-insulin-dependent diabetes mellitus 3 in NSY; BTA17LW, bovine chromosome 17 live weight; Imfq1,
intramuscular fat QTL 1; p, paternal effect; m, maternal effect; NA, Not available.
* Synteny relationships established according to the following references (60 – 64).
† Also observed in the cross CAST/Ei ⫻ C57BL/6J (327).
‡ Also observed in the CAST/Ei ⫻ C57Bl/6J F2 intercross (591).
§ Also observed in the cross (C3H/He ⫻ A/J) ⫻ M. spretus (592).
¶ Replicated.
genes have reported significant associations. Of these, 49
studies (32 candidate genes) were published during the past
year. Body weight, BMI, overweight, and obesity were
associated with DNA sequence variation in LEPR (65,66),
GHRL (67), PPARG (68), APM1 (69,70), PPARGC1 (71),
CART (72), ADRB2 (73,74), SERPINE1 (75), ADRB3
(76,77), CYP7A1 (78), ADRB1 (79), IGF2 (80), INS (80),
TH (80), DRD2 (81), GNB3 (82), HTR2A (83), SAH (84),
AGRP (85), FIZZ3 (86), and TNRC11 (87). Body-fatnessrelated phenotypes (body-fat mass, percentage of body fat,
and skinfolds) showed associations with markers on
PPARGC1 (71), ADRB2 (74), ADRA2A (88), ADRB1
(79), IGF2 (89), AGRP (85), LIPE (90), and MC3R (91).
Phenotypes reflecting body-fat distribution (abdominal visceral fat, waist-to-hip ratio, waist circumference) were associated with APM1 (69) and GCGR (92). Resting energy
expenditure and respiratory quotient were associated with
UCP3 (93,94) and MC3R (91) markers, whereas adipocyte
lipolysis showed associations with polymorphisms in
CAPN10 (117), LEP (95), and GNB3 (96,97).
324
OBESITY RESEARCH Vol. 11 No. 3 March 2003
Thirteen studies reported associations between candidate
genes and changes in body weight. The LEPR (65), AGT
(98), ADRA2B (99), and ADRB2 (100) loci showed associations with spontaneous weight gain over time. Markers in
the UCP3 (101) and GNB3 (102) loci were associated with
endurance-training-induced changes in the sum of eight
skinfolds and fat mass, respectively, whereas the ADRB3
locus was associated with diet-induced weight changes in
Chinese children (103). DNA sequence variation in the
PPARG locus showed associations with weight loss during
a 3-year lifestyle intervention (104). Markers in the HTR2C
locus were associated with antipsychotic-drug-induced
weight gain in psychiatric patients (105) and with weight
loss in teenage girls (106).
In addition to the positive studies summarized above, we
identified 49 studies reporting lack of associations between
candidate genes and obesity-related phenotypes. Among
these studies, the most frequent ones were those pertaining
to markers of PPARG (107–110) and FIZZ3 (111–114)
(four studies each), CAPN10 (115–117), GNB3
Figure 1: The 2002 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 is a hybrid, consisting of an updated 850-band-resolution cytogenetic map overlaid with
the draft human genome sequence, build 30, 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. 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 Web site
(http://obesitygene.pbrc.edu).
OBESITY RESEARCH Vol. 11 No. 3 March 2003
325
326
OBESITY RESEARCH Vol. 11 No. 3 March 2003
OBESITY RESEARCH Vol. 11 No. 3 March 2003
327
328
OBESITY RESEARCH Vol. 11 No. 3 March 2003
OBESITY RESEARCH Vol. 11 No. 3 March 2003
329
330
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OBESITY RESEARCH Vol. 11 No. 3 March 2003
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 6. Evidence for the presence of an association between markers of candidate genes with BMI, body fat, and
other obesity-related phenotypes
Gene
Location
TNFRSF1B
NR0B2
LEPR
1p36.3-p36.2
1p36.1
1p31
HSD3B1
LMNA
1p13.1
1q21.2-q21.3
ATP1A2
1q21-q23
APOA2
AGT
1q21-q23
1q42-q43
ACP1
2p25
APOB
2p24-p23
POMC
2p23.3
ADRA2B
2p13-q13
IRS1
2q36
CAPN10
GHRL
2q37.3
3p26-p25
PPARG
3p25
Cases
(N)
Phenotype
p value
217
217
20
308
130
502
267
62
118
179
387
220
335
336
132
48
306
47
186
122
156
624
316
94
135
75
265
232
181
56
337
75
166
126
1748
156
148
192
65
820
333
973
752
869
121
141
375
921
838
70
BMI, leptin
Obesity (early-onset)
%FAT
FFM (in BMI ⱖ 27 kg/m2)
Obesity (extreme in children)
BMI, FM
BMI, abdominal sagittal diameter
ATF, ASF
BMI
⫺⌬BW (overweight women)
FM, BMI
BMI, FM, leptin (postmenopausal women)
⬎BW, ⬎FM, ⬎BMI (women)
Overweight/obesity
⌬SF(⌺6) (12 years)
Leptin, leptin: BMI ratio, lipodystrophy
BMI, WHR, leptin (Canadian Oji-Cree)
Familial partial lipodystrophy
BW, BMI, WC, SF (subscapular)
%FAT, RQ
RQ (young adults)
WC
WHR
FM (women ⱖ42 years old)
⫹⌬BW (3-year follow-up)
BMI (children)
BMI (NIDDM subjects)
BMI
BMI
%FAT, fat (abdominal)
Leptin (Mexican Americans)
Leptin (obese children)
BMR (obese nondiabetics)
⌬BW (5-year in nondiabetics)
BMI, ⌬BMI (African Americans)
Leptin (obese subjects)
ADRB3 activity (adipocytes; overweight)
Obesity (women)
BMI (tall obese children)
Leptin (obese subjects)
BMI (middle-aged)
BMI (elderly)
⌬BMI (obese men)
⌬BMI (lean men)
BMI
BW, BMI, LBM, FM, WC, HC
Obesity (severe with early onset)
BMI, WC, leptin (Mexican Americans)
BMI, BW, WC, height
⫹⌬weight (regain after loss)
⬍0.05
0.009
0.003
0.03 to 0.05
0.02 to 0.04
0.005 to 0.03
0.04 to 0.05
0.03 to 0.04
0.01 to 0.04
0.006
0.003 to 0.03
0.0001 to 0.009
0.01 to 0.05
0.009 to 0.01
0.04
⬍0.05
⬍0.05
⬍0.0001
0.002 to 0.02
⬍0.05
0.0001
0.03
0.007
0.008 to 0.02
0.006
0.02
0.002
0.005
0.05
0.04
0.001
⬍0.03
0.01
0.04
0.04 to 0.05
0.03
0.004
⬍0.05
0.001
0.001
0.03
0.02
0.002
0.008
0.03
0.002 to 0.05
⬍0.05
0.02 to 0.03
0.002 to 0.04
⬍0.01
References
(384)
(385)
(386)
(387)
(388)
(389)
(390)
(391)
(392)
(393)
(394)
(65)
(66)
(395)
(396)
(397)
(398)
(399)
(400)
(401)
(402)
(403)
(404)
(98)
(405)
(406)
(407)
(408)
(409)
(410)
(411)
(412)
(99)
(413)
(414)
(117)
(415)
(67)
(416)
(417)
(418)
(419)
(420)
(421)
(422)
(423)
(424)
OBESITY RESEARCH Vol. 11 No. 3 March 2003
333
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 6 (continued)
Gene
Location
APOD
APM1
3q26.2-qter
3q27
CCKAR
PPARGC1
FABP2
4p15.2-p15.1
4p15.1
4q28-q31
UCP1
4q28-q31
NPY5R
CART
4q31-q32
5q13.1
GRL
5q31-q32
ADRB2
5q31-q32
TNFA
6p21.3
HSPA1B
HTR1B
ESR1
6p21.3
6q13
6q25.1
334
Cases
(N)
Phenotype
p value
619
119
225
464
114
413
614
371
1296
467
395
507
123
163
113
526
24
74
612
528
51
262
480
12
135
140
508
836
574
277
826
224
180
284
236
494
286
24
366
63
38
363
1351
110
378
1047
176
136
517
98
216
BMI
⫹⌬weight (10-year)
⫺⌬weight (3-year lifestyle intervention)
BMI, obesity
BMI
BW, WC (Japanese)
BW (whites)
BMI
%FAT, leptin
BMI, FM, WC, HC (women)
Fat (abdominal)
BMI, %FAT
Fat (high gainers over 12 years)
⫺⌬BW, ⫺⌬BMI
⫺⌬BW (Japanese women)
BMI (overweight women)
BW (recovery 4 months after overfeeding)
Obesity (BMI 40 to 47 kg/m2; Pima Indians)
WHR (men)
BMI, obesity
AVF (lean subjects)
BMI, WHR, WC, leptin
AVF
⫹⌬BW (100 days of overfeeding)
WHR (males)
BMI, FM, fat cell volume
BMI (Japanese)
BW, BMI, WC, WHR, HC (French men)
BMI (Japanese)
BMI (Japanese men)
Obesity, BMI, WC, HC, WHR
BMI ⬎ 35 kg/m2 (men)
BMI
Leptin
Lipolysis
⫹⌬BW (childhood to adulthood; males)
⫹⌬BW
⫹⌬BW, ⬎SF(⌺8), ⬎leptin (overfeeding)
BMI (women)
BMI, FM
%FAT
BMI
BMI
Obesity (27 ⬍ BMI ⬍ 35 kg/m2)
BMI, %FAT (women)
Obesity
BMI
WC (women)
Obesity
BMI (women with bulimia nervosa)
Obesity (android type)
0.04
0.009
0.04
0.01 to 0.03
0.006
0.03 to 0.004
0.03
0.02
0.003 to 0.04
0.005 to 0.03
0.008
0.01
0.05
⬍0.05
0.001
0.02
0.05
⬍0.05
0.002
0.008 to 0.04
0.003 ⬍ p ⬍ 0.007
0.001 to 0.039
0.001
0.01
0.01
0.001 ⬍ p ⬍ 0.009
0.001
⬍0.002
0.009 to 0.003
0.004
0.05 to 0.01
0.01
0.003 to 0.02
0.03
0.02
⬍0.01
0.04 to 0.05
⬍0.03
⬍0.01
⬍0.05
0.02
0.01
0.004
0.02
0.02
0.04
0.01
0.04
0.0002
0.001
0.0002
OBESITY RESEARCH Vol. 11 No. 3 March 2003
References
(425)
(426)
(104)
(68)
(427)
(69)
(70)
(428)
(71)
(429)
(430)
(431)
(432)
(433)
(434)
(93)
(435)
(436)
(72)
(437)
(438)
(439)
(440)
(441)
(442)
(443)
(444)
(445)
(446)
(447)
(448)
(449)
(450)
(451)
(100)
(452)
(453)
(73)
(74)
(454)
(455)
(456)
(457)
(458)
(459)
(460)
(461)
(462)
(463)
(464)
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 6 (continued)
Gene
Location
GCK
NPY
7p15.3-p15.1
7p15.1
PON2
SERPINE1
LEP
7q21.3
7q21.3-q22
7q31.3
Cases
(N)
58
369
595
100
505
168
84
395
117
103
211
233
LPL
8p22
ADRB3
8p12-p11.2
CYP7A1
CBFA2T1
SH3D5
ADRA2A
8q11-q12
8q22
10q23.3-q24.1
10q24-q26
ADRB1
10q24-q26
236
249
587
128
185
335
350
49
295
254
131
398
83
53
586
56
261
211
179
76
553
213
802
476
1675
979
457
154
313
47
1102
281
770
72
476
213
931
Phenotype
p value
References
BW (at birth; males)
BW (at birth)
BMI, WHR
BW (at birth; Trinidadian neonates/South Asian)
Obesity
⫺⌬BW
BW
Leptin
Leptin
Leptin (response to diet)
BMI, BW
Obesity (women)
Leptin (obese women)
Leptin (secretion)
BMI (leanness)
⌬BMI-FM-%FAT (training; white women)
BMI (women)
⫹⌬BW (25 years)
⫹⌬BW (20 years), weight (current)
WHR (women)
BMI
BMI
BMI
Obesity (early onset)
FM, AVF
AVF/ASF, BMI
BMI (CAD patients)
Obesity
BMI, HC (women)
BMI, FM, WC
BMI
Obesity (moderate)
⌬BMI (during pregnancy)
FM (Thai males)
Obesity (Japanese children)
ATF, ASF
BMI
BMI (men)
Obesity, BMI, %fat
WHR (men ⬎53 years old)
Overweight (20-year follow-up)
Obesity (sedentary state)
Obesity (20 to 35 years old)
⫹⌬BW (dietary intervention; obese children)
BMI
%FAT, BMI, WC, HC
Obesity
TER (women)
ATF, ASF
TER (blacks)
BW, BMI
0.002
0.03
0.03 to 0.04
⬍0.05
0.002 to 0.006
0.006 ⬍ p ⬍ 0.007
0.05
0.02
0.04
(465)
(466)
(467)
(468)
(75)
(469)
(470)
(471)
(472)
0.005
⬍0.05
0.02 to 0.04
⬍0.05
0.05
0.01 to 0.03
⬍0.02
0.01
0.007 ⬍ p ⬍ 0.03
0.02
0.009
0.03
⬍0.05
0.002
⬍0.01
0.02 ⬍ p ⬍ 0.03
⬍0.05
⬍0.05
⬍0.03
⬍0.05
⬍0.05
0.02
0.006 to 0.02
⬍0.05
0.02
0.02 to 0.03
0.02
0.05
⬍0.05
⬍0.05
⬍0.05
0.05
⬍0.05
⬍0.05
⬍0.05
0.0002 ⬍ p ⬍ 0.02
⬍0.05
0.002
0.01 to 0.003
0.04
⬍0.05
(473)
(474)
(475)
(95)
(476)
(477)
(478)
(479)
(480)
(481)
(482)
(483)
(484)
(485)
(486)
(487)
(488)
(489)
(490)
(491)
(492)
(493)
(494)
(495)
(496)
(448)
(497)
(478)
(498)
(499)
(76)
(77)
(103)
(78)
(500)
(501)
(502)
(448)
(88)
(79)
OBESITY RESEARCH Vol. 11 No. 3 March 2003
335
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 6 (continued)
Gene
Location
SUR1
IGF2
11p15.1
11p15.5
INS
11p15.5
TH
UCP2
11q15.5
11q13
UCP3
11q13
APOA4
11q23
DRD2
11q22.2-q22.3
GNB3
12p13
336
Cases
(N)
214
232
1474
427
2734
758
52
1152
238
2734
2734
82
790
220
143
60
105
813
41
791
596
949
120
382
401
734
116
220
208
419
64
24
393
73
375
613
392
383
176
320
990
197
1950
213
230
181
20
130
Phenotype
p value
BW, BMI, FM
Obesity (morbid)
BMI
FM
BW
BW (at birth)
WHR (obese women)
BMI
Obesity (childhood; paternal transmission)
BW
BW
24-h SMR
BMI (⬎45 years old)
BMI (South Indian women)
BMI (South Indian parents; NIDDM probands)
24-h EE, 24-h SPA, sleeping SPA, 24-h NPRQ, 24-h
FATOX
BW, BMI, %overweight, %FAT, FM, SF(⌺4)
Obesity (BMI ⬎30 kg/m2)
⫹⌬BW, ⫹⌬FM (peritoneal dialysis patients)
BMI
Obesity
Obesity
BMI, RQ, NPRQ, FATOX/LBM (African American)
BMI (current, max.), BW (diet therapy; very obese)
BMI (morbidly obese subjects)
BMI, FM, %FAT, SF(⌺6), leptin
WHR (South Indian women)
WHR (South Indian women)
WHR (European women)
BMI
%FAT (women)
RMR
⌬SF(⌺8) (training)
REE (black women)
BMI, WHR (young men; no family history of MI)
BMI, %FAT
BW
SF (iliac, triceps)
Obesity (BMI ⬎30 kg/m2)
24-h EE
SMR
Obesity
BMI (hypertensives)
BW, BMI (males; white, Chinese, African)
BMI, WC, HC, SF (Nunavut Inuit)
BMI (primiparous women)
BW (at birth; mothers’ genotype)
Lipolysis (in vitro)
BMI
⬍0.05
0.02
0.02
⬍0.05
0.001
0.009
0.005
⬍0.0002
⬍0.05
0.0014
0.01
0.007 ⬍ p ⬍ 0.04
0.04
0.02
⬍0.001
0.005 to 0.05
OBESITY RESEARCH Vol. 11 No. 3 March 2003
0.001 to 0.05
0.002
⬍0.05
0.03
0.007
0.006
0.008 to 0.04
0.02 to 0.04
0.0037
⬍0.0005
0.03
0.04
0.04
0.004
0.03
⬍0.01
⬍0.01
0.01
0.004
0.004 to 0.02
0.002
0.002 to 0.04
0.002 to 0.003
0.03
0.04
0.03
0.02
0.001 to 0.05
⬍0.05
0.01
0.02
0.01
⬍0.001
References
(503)
(504)
(89)
(80)
(505)
(506)
(507)
(508)
(80)
(80)
(509)
(510)
(511)
(512)
(513)
(514)
(515)
(516)
(517)
(518)
(519)
(520)
(521)
(522)
(523)
(93)
(101)
(94)
(524)
(525)
(526)
(527)
(528)
(529)
(81)
(530)
(531)
(532)
(533)
(534)
(96)
(82)
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 6 (continued)
Location
Cases
(N)
IGF1
12q22-q23
250
114
502
CD36L1
HTR2A
12q24.1-q24.3
13q14-q21
SAH
AGRP
GCGR
MC5R
MC4R
16p13.11
16q22
17q25
18p11.2
18q22
FIZZ3
INSR
LDLR
19p13.3
19p13.3-p.13.2
19p13.3
LIPE
19q13.1-q13.2
APOE
19q13.2
GYS1
ADA
MC3R
19q13.3
20q12-q13.11
20q13.2-q13.3
PPARA
TNRC11
HTR2C
22q12-q13.1
Xq13
Xq24
Gene
288
276
264
4059
183
950
156
156
268
411
75
84
112
83
270
131
380
117
110
257
181
64
164
130
273
314
168
154
68
589
117
148
Phenotype
p value
⌬FM, ⌬%FAT (training)
Lipolysis (subcutaneous; adrenoceptor-mediated)
FM, %FAT, FFM
⌬FFM (training)
BMI (lean women)
Dietary energy, carbohydrate/alcohol intake (obese)
BMI, WHR, abdominal sagittal diameter
BMI
BMI, FM, %FAT (white parents)
WC, WHR, sagittal abdominal diameter
BMI (females)
FM, %FAT, FFM (females)
WHR, BMI
BMI, obesity
Obesity (BMI ⬎26 kg/m2; hypertensives)
BMI (hypertensives)
BMI (hypertensives)
BMI (normotensives)
Obesity (BMI ⱖ26 kg/m2)
BMI, SF (triceps, subscapular), arm fat index
Obesity
WHR, lipolysis
BMI (women)
%FAT, SF(⌺8) (white women)
BMI, FM, %FAT, SF(⌺8) (black women)
Leptin
WC (women with a family history of diabetes)
Obesity
BMI (NIDDM subjects)
FM, %FAT (normal weight)
FM, %FAT, BMI, RQ (overweight)
BMI (type 2 diabetics)
Obesity
BMI (⬎28 kg/m2)
⫹⌬BW (antipsychotic-induced)
⫺⌬BW (teenage women)
0.006 to 0.01
0.004 to 0.02
⬍0.05
0.005
0.004 to 0.03
0.03 to 0.05
0.02 to 0.04
0.007
0.003 to 0.02
0.001 to 0.04
0.003
0.002 ⬍ p ⬍ 0.004
0.02 to 0.05
0.01 to 0.04
0.05
0.004
0.04
0.008
0.02
0.001 to 0.02
0.002
0.02 to 0.001
0.012
0.005 to 0.01
0.0009 to 0.01
0.02
⬍0.05
0.03
0.0004 to 0.01
⬍0.0005
0.0001 to 0.009
0.02
0.001
0.009 to 0.02
0.0003
0.0001
References
(102)
(97)
(535)
(536)
(537)
(83)
(84)
(85)
(92)
(538)
(538)
(539)
(86)
(540)
(541)
(542)
(543)
(544)
(545)
(546)
(547)
(548)
(90)
(523)
(549)
(550)
(551)
(91)
(552)
(87)
(553)
(105)
(106)
Status as of October 2002.
FM, fat mass; %FAT: percentage of body fat; NIDDM: non-insulin-dependent diabetes; RQ, respiratory quotient; WC, waist circumference; HC, hip
circumference; SF, skinfolds; WHR, waist to hip ratio; FFM, fat free mass; LBM, lean body mass; ⌬, change; ⫹⌬, gain; ⫺⌬: loss; TER, trunk to extremity
ration skinfolds; ATF, abdominal total fat; ASF, abdominal subcutaneous fat; AVF, abdominal visceral fat; 24-h EE, 24-hour energy expenditure; REE,
resting energy expenditure; 24-h SMR, 24-hour sleeping metabolic rate; 24-h SPA, 24-hour spontaneous physical activity; FATOX, fat oxidation; NP,
non-protein; CAD, cardiovascular disease; ⌺, sum of skinfolds.
(102,118,119), LEPR (120 –122), and TNF (65,123,124)
(three studies), and ADRB3 (65,125), LEP (66,126), MC4R
(10,127), and POMC (128,129) (two studies). Other markers yielding negative findings were those related to ACE
(130), ADRA2A (131), ADRB1 (132), ADRB2 (133), AGT
(134), APOE (135), CETP (136), EDN1 (137), ENPP1
(138), FABP2 (139), GABRA6 (140), GHRL (141),
HSD3B1 (142), LIPE (143), NPY (66), NPYY1 (144),
PPARGC1 (71), PTPN1 (145), SLC2A4 (146), TNFRSF1B
(147), UCN (148), and UCP1 (149).
OBESITY RESEARCH Vol. 11 No. 3 March 2003
337
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 7. Evidence for the presence of linkage with obesity-related phenotypes
Gene and/or markers*
Location
N pairs
Phenotypes
p or Lod value
D1S468,508
PGD
LEPR
D1S193,200,476
Q223R, IVS3CA,
IVS16CTTT
D1S1665
D1S550
D1S534
ATP1B1
ATP1A2
N/A
D1S1679
1p36.3-p36.2
1p36.2-p36.13
994 subjects; 37 pedigrees
⬎168
BMI (females)
SF (suprailiac)
2.2 ⬍ Lod ⬍ 2.5
p ⫽ 0.03
(155)
(554)
1p35-p31
1p31
202–251
268–324
BMI, SF (⌺6), FM
BMI, SF (⌺6), FM, FFM
0.009 ⬍ p ⬍ 0.02
0.005 ⬍ p ⬍ 0.05
(555)
1p31-p21
Leptin
24-h RQ
ASF
RQ
RQ
adipocyte size
BMI
Lod ⫽ 3.4
Lod ⫽ 2.8
Lod ⫽ 2.3
p ⫽ 0.04
p ⫽ 0.02
Lod ⫽ 1.7
Lod ⫽ 1.8
ACP1
2p25
D2S2337
D2S1788
2p23.3
2p21
D2S165, 367
2p22-p21
D2S411
IGKC
D2S1399,1334
IRS1, D2S434
D3S2387
D3S3608
D3S1259
D3S2432
D3S1768
D3S1764
D3S2427
2p14
2p12
2q22.1
2q36
3p26.3
3p25
3p24.2-p22
198 subjects; 18 pedigrees
236
521 subjects; 156 families
94
289
295 subjects; 164 families
1184 subjects; 317 sibships
3027 subjects; 401 families
⬎300
⬎168
264
⬎5000 (relative)
720 subjects; 230 families
337 subjects
264
1100 subjects; 170 families
668 subjects; 99 families
⬎168
668 subjects; 99 families
668 subjects; 99 families
668 subjects; 105 families
624 subjects; 28 families
1055
377
580 families
924
2209 subjects; 507 families
BMI
SF (triceps)
Leptin
FM, leptin
Leptin, BMI
Leptin
Leptin
Adiponectin
ASF (whites)
SF (triceps)
AVF (whites)
AVF (whites)
ASF (blacks)
Eating behavior: restraint
BMI (white)
%FAT
BMI (Finnish)
BMI (black)
BMI
WC
BMI (African American)
BMI
ASF (blacks)
ASF
BMI (females)
TER
ASF (blacks)
ASF
Adiponectin
BMI (African American)
Leptin
BMI
Obesity
BMI, leptin
ASF, ATF (whites)
BMI (⬎27 kg/m2)
TER
p ⫽ 0.004
p ⫽ 0.02
Lod ⫽ 2.0
Lod ⫽ 4.9/2.8
0.008 ⬍ p ⬍ 0.03
Lod ⫽ 7.5
Lod ⫽ 2.4/2.7
Lod ⫽ 2.7
Lod ⫽ 1.9
p ⫽ 0.03
2.0 ⬍ Lod ⬍ 2.3
1.9 ⬍ Lod ⬍ 2.5
Lod ⫽ 2.2
Lod ⫽ 2.5
Lod ⫽ 2.0
Lod ⫽ 2.0
Lod ⫽ 3.4
Lod ⫽ 3.4
Lod ⫽ 3.3
Lod ⫽ 2.4
Lod ⫽ 1.8
Lod ⫽ 3.4
Lod ⫽ 2.5
Lod ⫽ 2.3
6.1 ⬍ Lod ⬍ 9.2
p ⫽ 0.02
Lod ⫽ 2.3
Lod ⫽ 1.8
Lod ⫽ 4.1
Lod ⫽ 1.9
Lod ⫽ 2.9
Lod ⫽ 1.7
p ⫽ 0.03
0.0004 ⬍ p ⬍ 0.006
1.9 ⬍ Lod ⬍ 2.1
p ⫽ 0.009
p ⫽ 0.02
D3S1311
D4S2397
D4S2632, 3350
GYPA
D4S2431
D4S2417
D5S817
1p11.2
1q22-q25
1q21-q23
1q21-q23
1q24.2
3q21
3q22.1
3q27
3q29
4p15-p14
4q28.2-q31.1
4q31.22-q32.1
5p15.3
D5S426
D5S2489, 2500
ISL1
5p11
5q12-q13
5q22.3
D5S658, 1480
GRL
ADRB2
5q31.2-q31.3
5q31-q32
5q31-q32
338
618 subjects; 202 families
4821
668 subjects; 105 families
521 subjects; 156 families
994 subjects; 37 pedigrees
160
668 subjects; 105 families
521 subjects; 156 families
1100 subjects; 170 families
618 subjects; 202 families
264
1526
226
284
668 subjects; 99 families
88
66
OBESITY RESEARCH Vol. 11 No. 3 March 2003
References
(387)
(556)
(557)
(558)
(400)
(401)
(559)
(153)
(560)
(554)
(561)
(562)
(563)
(410)
(564)
(565)
(151)
(554)
(151)
(151)
(151)
(156)
(154)
(566)
(567)
(154)
(568)
(152)
(154)
(151)
(558)
(155)
(569)
(151)
(558)
(565)
(152)
(564)
(150)
(570)
(151)
(571)
(502)
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 7 (continued)
Gene and/or markers*
Location
N pairs
Phenotypes
p or Lod value
MFD154
5q35
BMI
Lod ⫽ 1.8
(153)
BF
TNFA
TNFir24, D6S273,291
GLO1
D6S1959
D6S276
D6S271
D6S403,1003
D6S264
NPY
6p21.3
6p21.3
1184 subjects; 317 sibships;
3027 subjects; 401 families
⬎168
⬎255
SF (triceps, subscapular, suprailiac)
%FAT
0.01 ⬍ p ⬍ 0.03
0.002 ⬍ p ⬍ 0.05
(554)
(455)
(554)
(152)
(156)
(572)
(157)
(157)
(573)
D10S197
D10S220
N/A
D10S204,193,17,81,
TCF8
D10S208, 582, 107
10p12-p11
10p12-p11
⬎168
618 subjects; 202 families
624 subjects; 28 families
1199
261 subjects; 27 pedigrees
261 subjects; 27 pedigrees
545
170
1070
336
1055
47
60
60
545
545
46
59
88
545
521 subjects; 156 families
1184 subjects; 317 sibships;
3027 subjects; 401 families
672 subjects; 28 pedigrees
402
668 subjects; 105 families
470 subjects; 10 pedigrees
994 subjects; 37 pedigrees
⬎5000 (relative)
522 subjects; 99 families
521 subjects; 156 families
⬎168
522 subjects; 99 families
⬎168
522 subjects; 99 families
1526
264
672 subjects; 28 pedigrees
1100 subjects; 170 families
386 subjects; 93 families
AFM198zb
SUR1, D11S419
C11P15_3
CCKBR
10q-ter
11p15.1
11p15.2
11p15.4
862
212
198
67
668
221
D7S3051
D7S1808
D7S2847
LEP
D7S680, 530
D7S514
6p21.3-p21.1
6p21.3-p21.1
6q24.1-q24.2
6q25.2-q26
7p15.1
7p15.3-p15.2
7q22.3
7q31.3
D7S495
D7S504
D7S1875
D7S1875
GATA443C11,
D7S1804
D7S640, 636
KEL
D7S3070, NOS3
ADRB3, D8S1121
D8S282
D8S1110
D8S556
D9S1122, 257
ORM1
D9S158
AK1
D10S1435, 189
7q31.3-q32.3
7q31-q36
7q33
7q36.2
8p12-p11.2
8p11.22
8q11.1
8q23.3
9q22.1
9q31-q32
9q34.3
9q34.1
10p15
subjects; 170 families
subjects; 43 families
subjects; 18 pedigrees
subjects; 105 families
References
SF (suprailiac), BW
%FAT (African American)
Eating behavior: restraint
Leptin
BMI, leptin, insulin (PCA)
BMI, leptin, insulin (PCA)
BW, SF, WC, HC, height (PCA)
Obesity
BMI (Asian)
FFM
BMI (white)
body fat
BMI (⬎35 kg/m2)
BMI (⬎35 kg/m2)
BMI, SF, FM, WC
BMI, SF, FM, WC
BMI (⬎85th percentile)
BMI (ⱖ40 kg/m2)
BMI
WHR
ASF
BMI
0.004 ⬍ p ⬍ 0.05
Lod ⫽ 2.7
Lod ⫽ 2.3
Lod ⫽ 2.1
Lod ⫽ 4.2
Lod ⫽ 4.9
p ⫽ 0.05
p ⫽ 0.04
Lod ⫽ 2.7
Lod ⫽ 2.7
Lod ⫽ 2.4
p ⫽ 0.008
0.002 ⬍ p ⬍ 0.009
0.002 ⬍ p ⬍ 0.009
0.0001 ⬍ p ⬍ 0.02
0.0001 ⬍ p ⬍ 0.02
p ⫽ 0.001
p ⫽ 0.04
p ⫽ 0.04
p ⫽ 0.009
Lod ⫽ 2.0
3.2 ⬍ Lod ⬍ 4.9
(154)
(574)
(154)
(575)
(576)
(576)
(577)
(577)
(578)
(579)
(580)
(573)
(558)
(153)
Leptin (adjusted for BMI)
BMI, SF(⌺6)
⌬ATF (black; training)
BMI
BMI (males)
Leptin
BMI
ASF
SF (suprailiac)
BMI
SF (suprailiac)
BMI, FM
BMI
Obesity
Leptin (adjusted for BMI)
Adiponectin
Obesity
Lod ⫽ 1.9
⬍0.0001
2.3 ⬍ Lod
Lod ⫽ 3.2
Lod ⫽ 2.0
Lod ⫽ 2.2
Lod ⫽ 2.0
2.1 ⬍ Lod
p ⫽ 0.03
Lod ⫽ 2.3
p ⫽ 0.01
2.1 ⬍ Lod
Lod ⫽ 1.7
Lod ⫽ 4.9
Lod ⫽ 2.7
Lod ⫽ 1.9
1.1 ⬍ Lod
(581)
(569)
(151)
(582)
(155)
(562)
(583)
(558)
(554)
(583)
(554)
(583)
(150)
(564)
(581)
(565)
(584)
Obesity (white)
Obesity (African American)
BMI
BMI (ⱖ27 kg/m2)
ASF (black)
Leptin
0.03 ⬍ p ⬍ 0.0005
(585)
Lod ⫽ 3.3
p ⫽ 0.003
Lod ⫽ 1.9
p ⫽ 0.01
(556)
(503)
(151)
(570)
⬍ 2.5
⬍ 2.4
⬍ 2.7
⬍ 2.5
OBESITY RESEARCH Vol. 11 No. 3 March 2003
339
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 7 (continued)
Gene and/or markers*
Location
N pairs
Phenotypes
p or Lod value
GATA34E08
UCP2/UCP3
D11S2000
D11S2366
11p14.1
11q13
11q22
D11S976
D11S4464, 934, 912
D11S912
D11S1998, 4464
D12S1042
IGF1
IGF1
D12S2078, 1045
D13S175, 221
D13S257
11q23-q24
668 subjects; 105 families
240 (relative)
277
277
451
236
479 subjects; 14 pedigrees
1766
1526
522 subjects; 99 families
521 subjects; 156 families
352
521 subjects; 156 families
580 Finnish families
1184 subjects; 317 sibships
3027 subjects; 401 families
194
521 subjects; 156 families
522 subjects; 99 families
1100 subjects; 170 families
672 subjects; 28 pedigrees
ASF (black)
RMR
%FAT
%FAT
%FAT
24-h EE
BMI (males)
BMI
BMI
BMI, FM
ASF
AVF
ASF
BMI (diabetic subjects)
BMI
Lod ⫽ 1.8
p ⫽ 0.000002
Lod ⫽ 2.8
Lod ⫽ 2.8
Lod ⫽ 2.1
Lod ⫽ 2.0
2.6 ⬍ Lod ⬍ 2.8
Lod ⫽ 3.6
Lod ⫽ 2.7
Lod ⫽ 2.2
Lod ⫽ 1.9
p ⫽ 0.02
1.5 ⬍ Lod ⬍ 2.9
Lod ⫽ 3.3
Lod ⫽ 3.2
SF(⌺6), %FAT
ASF
BMI, FM, FFM
Adiponectin
WC
Leptin (adjusted for BMI)
ASF (blacks)
BMI (blacks)
BMI
p ⬍ 0.04
Lod ⫽ 1.9
1.7 ⬍ Lod ⬍ 2.4
Lod ⫽ 3.2
Lod ⫽ 1.8
Lod ⫽ 2.5
Lod ⫽ 2.4
Lod ⫽ 2.2
Lod ⫽ 1.7
(569)
(558)
(583)
(565)
(581)
FFM
BMI, Leptin
BMI (white)
Leptin
Leptin
Adiponectin
BMI (white)
ASF
BMI, SF(⌺6), FM, FFM, %FAT,
RMR
RQ
Obesity
FFM
FFM
%FAT
Obesity
Leptin (white)
BMI
BMI (females)
24-h RQ
BMI, SF(⌺6)
BMI, SF(⌺6), FM, %FAT
BMI, SF(⌺6), FM, %FAT
BMI, SF(⌺6), FM
BMI (⬎30 kg/m2), %FAT
ASF (whites)
2.0 ⬍ Lod ⬍ 3.6
Lod ⫽ 1.7
Lod ⫽ 2.6
Lod ⫽ 2.0
Lod ⫽ 5.0
Lod ⫽ 1.7
Lod ⫽ 2.5
1.5 ⬍ Lod ⬍ 2.2
0.001 ⬍ p ⬍ 0.02
(574)
(581)
(154)
(572)
(568)
(565)
(154)
(558)
(538)
p ⫽ 0.04
0.001 ⬍ p ⬍ 0.003
Lod ⫽ 3.6
Lod ⫽ 3.6
Lod ⫽ 2.3
Lod ⫽ 2.4
p ⫽ 0.0009
Lod ⫽ 3.5
2.0 ⬍ Lod ⬍ 2.2
Lod ⫽ 3.0
0.001 ⬍ p ⬍ 0.02
0.004 ⬍ p ⬍ 0.02
0.004 ⬍ p ⬍ 0.02
0.008 ⬍ p ⬍ 0.02
3.0 ⬍ Lod ⬍ 3.2
Lod ⫽ 2.0
(538)
(588)
(574)
(574)
(557)
(589)
(583)
(158)
(155)
(557)
(569)
(326)
(326)
(326)
(590)
(151)
12p12.1
12q22-q23
12q24.3
13q11
13q14
ESD
D13S285
D14S283, 742, 1280
D14S608, 599
D14S276
D14S74, 280
D14S588
D14S617
GAAA1C11
13q14.1-q14.2
13q34
14q11.2-q13
14q22-q31
IGF1R, D15S652, 657
D16S510
GATA67G11
D16S265
D17S947
15q25-q26
16p
16q12.2
16q21
17p12
D17S2180, 1290, 1301
MC5R
17q21
18p11.2
MC4R
18q22
D18S535
D18S877
18q12
18q21
14q24
15q14
D18S115
LDLR
D20S438
D20S478,438,465,481
D20S601
ADA
20q12-q13.11
D20S17,120
MC3R
D20S107,211,149
D22S264
20q12-q13
20q13.2-q13.3
20q13
22q11.23
340
19p13
20p11.1-q11.1
20q11.2-q12
668 subjects; 105 families
800
1184 subjects; 317 sibships
3027 subjects; 401 families
336
672 subjects; 28 pedigrees
924
1199
2209 subjects; 507 families
1100 subjects; 170 families
924
521 subjects; 156 families
242 to 289
210
105
336
336
451
193
522 subjects; 99 families
1711 subjects; 103 pedigrees
994 subjects; 37 pedigrees
236
428
139 to 226
139 to 226
212 to 258
423
668 subjects; 99 families
OBESITY RESEARCH Vol. 11 No. 3 March 2003
References
(151)
(586)
(566)
(557)
(155)
(587)
(150)
(583)
(558)
(535)
(558)
(567)
(153)
(151)
(154)
(153)
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 7 (continued)
Gene and/or markers*
Location
N pairs
P1
DXS8099
DXS997-DXS1003
22q11.2-qter
Xp21
Xp22-p21
DXS1059
DXS6804
Xq23-q24
⬎168
994 subjects;
940 subjects;
208 subjects;
994 subjects;
193
37 pedigrees
190 families
43 families
37 pedigrees
Phenotypes
p or Lod value
References
BW
BMI (females)
WHR (white and black females)
p ⫽ 0.03
Lod ⫽ 2.6
Lod ⫽ 2.7
(554)
(155)
(159)
BMI (females)
Obesity
Lod ⫽ 2.0
Lod ⫽ 3.1
(155)
(589)
Status as of October 2002.
Chromosomal locations in bold indicate QTLs from genome-wide linkages; for these QTLs, the markers are given as indication and do not correspond
necessarily to the peak linkage.
NA, not available; RQ, respiratory quotient; RMR, resting metabolic rate; TER, trunk to extremity skinfolds ratio; WC, waist circumference; WHR,
waist-to-hip circumferences ratio; ASF, abdominal subcutaneous fat; AVF, abdominal visceral fat; SF, skinfolds; ⌺:, sum of skinfolds; ⌬, change; PCA,
principal component analysis; BW, body weight; %FAT: percent body fat; FM: fat mass; FFM: fat free mass; 24-h EE, 24-hour energy expenditure.
* See appendix for the complete name of the gene.
Linkage Studies
Table 7 presents a summary of the loci providing evidence of linkage with obesity-related phenotypes. We have
slightly reorganized the table by combining the gene and
marker information into one column. To highlight potential
replications among various studies, we have also combined
into one chromosomal region the overlapping QTLs uncovered from genome-wide scans. Finally, chromosomal locations indicated in bold mean that the linkage was derived
from genome-wide scans. The new linkages identified since
last year’s review were derived from eight genome-wide
scans (150 –157) and two scans of chromosomes 20 (158)
and X (159).
To examine the hypothesis that imprinted genes may
affect obesity, the evidence of linkage of BMI to loci
derived from either father or mother was tested in 846
individuals from 235 Pima Indian families (1526 sibpairs)
who were genotyped for 516 autosomal markers (150).
Evidence of linkage of BMI to maternally and paternally
derived alleles was found on chromosomes 5q12-q13 [linkage-odds (Lod) ⫽ 1.7] and 10p15 (Lod ⫽ 1.7), respectively]. In the combined model (non-parent-specific linkage),
evidence of linkage to BMI was found on 11q23-q24
(Lod ⫽ 2.7). A genome-wide linkage analysis of abdominal
fat measured by computed tomography before and after 20
weeks of endurance training was performed in the HERITAGE Family Study using a panel of 344 autosomal markers genotyped in 668 individuals from 99 white and 105
black families (151). For total abdominal fat, the best evidence of linkage was found on 5q31.2-q31.3. For abdominal
subcutaneous fat, the regions providing evidence of linkage
include 2p14, 5q31.2-q31.3, and 22q11.23 in whites and
3p26.3, 3q29, 4q31.22-q32.1, 11p15.2, 11p14.1, and 14q24
in blacks. Finally, for abdominal visceral fat, linkages were
found on 2q22.1 and 2q36 in whites. For the response to
training, the best evidence of linkage was found on 7q36.2
for changes in total abdominal fat in blacks. A genome-wide
scan for obesity was also conducted in 618 subjects from
202 African-American families living in the suburb of Chicago (152). Evidence of linkage with BMI and percentage
of body fat measured by bioelectric impedance was assessed
using a panel of 387 autosomal markers. Evidence of linkage for BMI was found on chromosomes 3q27 (Lod ⫽ 1.8)
and 5p15.3 (Lod ⫽ 1.9). For percentage of body fat, the
only significant evidence of linkage was found on chromosome 6p21.3-p21.1 (Lod ⫽ 2.7).
Several QTLs influencing body mass index were uncovered from two genome-wide scans involving a large collection of family samples. The first of these scans was performed in two samples of families participating in the
National Heart, Lung, and Blood Institute Family Heart
Study (153). The first sample included 1184 individuals
from 317 sibships genotyped for 243 markers, and the
second included 3027 subjects from 401 three-generation
families genotyped for 404 markers. Linkage analyses were
performed in each sample, as well as in the combined
sample, by putting the markers from each sample on a
common genetic map. Strong evidence of linkage with BMI
was found in each sample, as well as in the combined
sample on 7q31.3-q32.3 (3.2 ⬍ Lod ⬍4.9) near the leptin
gene. Evidence of linkage in the combined sample was also
observed on chromosomes 1q24.2 (Lod ⫽ 1.8), 5q35
(Lod ⫽ 1.8), 13q14 (Lod ⫽ 3.2), and 15q14 (Lod ⫽ 1.7).
The second scan for BMI was performed in eight samples of
families from the National Heart, Lung, and Blood Institute
Family Blood Pressure Program involving 6849 subjects
OBESITY RESEARCH Vol. 11 No. 3 March 2003
341
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Table 8. Evolution in the status of the human obesity gene map
Single-gene mutations*
KO and Tg
Mendelian disorders with map location
Animal QTLs
Human QTLs from genome scans
Candidate genes with positive findings
1994
1995
1996
1997
1998
1999
2000
2001
2002
—
—
8
7
—
9
—
—
12
9
—
10
—
—
13
24
—
13
2
—
16
55
3
21
6
—
16
67
8
29
6
—
20
98
14
40
6
—
24
115
21
48
6
—
25
165
33
58
6
38
33
168
68
71
From references (1– 8) and this review.
* Number of genes, not number of mutations.
(154). In the analyses of individual samples, the only significant evidence of linkage was found on 3q22.1 in a
sample of 924 black sibpairs (Lod ⫽ 3.4). Six additional
regions with weaker evidence of linkage in at least one of
the sample were found on chromosomes 3p24.2-p22,
7p15.3-p15.2, 7q22.3, 14q24, 16q12.2, and 17p12. Finally,
linkage with BMI was also tested by pooling data from
seven of the eight samples of families. This combined data
set included 2363 white sibpairs, 1990 black sibpairs, and
468 Mexican-American sibpairs. Asian sibpairs from the
eight samples were not included in the pooled data set
because the mean and the variance of the adjusted BMI
were quite different from the other ethnic groups. This
combined analysis revealed strong evidence of linkage on
3q27 (Lod ⫽ 3.4 with marker D3S2427), a region that was
shown to be linked with obesity phenotypes in three other
studies (see Table 7).
A genome scan for genes affecting severe obesity
(BMI ⱖ40 kg/m2) was performed in multigenerational
Utah pedigrees (155). Linkages were investigated using
628 markers and three different BMI phenotypes: a sexnonspecific phenotype (BMI), a female-only phenotype
(BMIf), and a male-only phenotype (BMIm). From 64
pedigrees with 1687 subjects, 37 pedigrees with 994
subjects were included in the analysis of BMIf and 14
pedigrees with 479 subjects were included in the analysis
of BMIm. A strong evidence of linkage with BMIf was
found on chromosome 4p15-p14 in a 10-cM interval
centered around marker D4S2632 (Lod ⫽ 6.1). After
increasing the marker density around the marker and the
size of the data set by adding 14 pedigrees, the evidence
of linkage increased to a Lod score of 9.2 at marker
D4S3350. Other regions showing significant evidence of
linkage with BMIf include 1p36.3-p36.2, 20q11.2-q12,
Xp21, and Xq23-q24. Evidence of linkage with BMIm
was found on 8p11.22 and 11q23-q24 (155). A previous
study undertaken in the same population tested evidence
of linkage of BMI to 48 chromosome 20 markers geno342
OBESITY RESEARCH Vol. 11 No. 3 March 2003
typed on 1711 individuals from 103 extended pedigrees
(158). The results provided evidence of linkage with BMI
in a 10-cM region around the centromere of chromosome
20 (Lod ⫽ 3.5 with D20S438 on 20p11.1-q11.1).
The first genome scan for phenotypes related to eating
behavior was published this year. Three eating behaviors
(restraint, disinhibition, and hunger) were measured in 624
subjects from 28 Amish families using the Three-Factor
Eating Questionnaire. The phenotypes were tested for linkage with a panel of 373 markers including 16 markers on
chromosome X (156). The strongest evidence of linkage
was found for restraint on chromosomes 3p25 (Lod ⫽ 2.5
with D3S1304) and 6p21.3-p21.1 (Lod ⫽ 2.3 with marker
D6S276). The peak linkages for disinhibition and hunger
did not reach the Lod score threshold of 1.7 (Lod ⫽ 1.6 near
marker D7S657 for disinhibition and Lod ⫽ 1.4 near marker
D3S1278 for hunger). A genome-wide scan for three factors
related to the metabolic syndrome was performed in 261
subjects from 27 Mexican-American families using 301
microsatellite markers (157). These three factors were obtained from a principal-component factor analysis of eight
phenotypes related to the metabolic syndrome and explained 68% of the variance in the eight phenotypes. Factor
1, which included BMI, leptin levels, and fasting insulin as
phenotypes, showed significant evidence of linkage to chromosomes 6q24.1-q24.2 (Lod ⫽ 4.2) and 6q25.2-q26
(Lod ⫽ 4.9).
Finally, 20 markers of the chromosome X were tested for
linkage with obesity phenotypes (BMI, percentage of body
fat, plasma leptin, waist and hip circumferences, as well as
waist-to-hip ratio) in two samples of families: 940 subjects
from 190 European-American families and 208 subjects
from 43 African-American families (159). Only the waistto-hip ratio in female subjects provided significant evidence
of linkage in the two samples as well as in the combined
sample in a 20-cM interval on Xp22-p21 between markers
DXS997 (47 cM) and DXS1003 (77.0 cM). The peak link-
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
age was found in African-American women at 73 cM with
a nonparametric linkage score of 2.7.
Table 7 indicates that 68 QTLs have now been uncovered
from 29 genome scans of obesity-related phenotypes. Eighteen of these QTLs have been replicated in at least two
studies on different populations; these QTLs are on chromosomes 1p31-p21, 2p22-p21, 3p24.2-p22, 3q27, 4p15p14, 4q31.22-q32.1, 5p15.3, 6p21.3-p21.1, 7p15.3-p15.2,
7q31.3-q32.3, 10p12-p11, 11q23-q24, 14q11.2-q13, 14q24,
17p12, 18q21, 20q11.2-q12, and Xq23-q24. The regions
harboring the largest number of replications include 11q23q24 with linkages in four different studies and 3q27,
6p21.3-p21.1, 10p12-p11, 17p12, and 18q21 with linkages
in three different studies.
Discussion
Figure 1 depicts the human obesity gene map and incorporates the loci from single-gene-mutation rodent models of
obesity, human obesity cases attributable to single-gene
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. It is becoming obvious that several
genomic regions are characterized by a high density of
concordant positive findings. As we near the completion of
the 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 course, some of
these loci 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.
Acknowledgments
The research of the authors on the genetics of obesity is
funded by the Canadian Institute Health Research (MOP13960) and the Pennington Biomedical Research Center. C.
Bouchard is supported by the George A. Bray Chair in
Nutrition. We thank Diane Drolet, M.Sc., for her dedicated
contribution to the compendium and the development of the
manuscript. Our gratitude goes to Marc J. Boudreaux and
Brandon Walts for their assistance with the data processing
associated with the production of Figure 1 and 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 on the
Web site of the Pennington Biomedical Research Center,
Human Genomics Laboratory, at http://obesitygene.pbrc.edu.
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The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2002 human obesity gene map*
Gene or locus
Name
Location
ACACB
ACH
ACP1
ADA
ADRB1
ADRB2
ADRA2A
ADRA2B
ADRB3
AGPAT2
AGRP
AGS
AGT
ANMA
AHO
AHO2
AK1
ALMS1
APM1
APOA2
APOA4
APOB
APOC1
APOD
APOE
ASIP
ATP1A2
ATP1B1
ATRN
Acetyl CoA Carboxylase 2
Achondroplasia
Acid phosphatase 1, soluble
Adenosine deaminase
Adrenergic, beta-1-, receptor
Adrenergic, beta-2-, receptor, surface
Adrenergic, alpha-2A-, receptor
Adrenergic, alpha-2B-, receptor
Adrenergic, beta-3-, receptor
Lysophosphatidic acid acyltransferase, beta
Agouti-related protein
Angelman syndrome with obesity
Angiotensinogen
Anisomastia
Albright hereditary osteodystrophy
Albright hereditary osteodystrophy 2
Adenylate kinase 1
Alstrom syndrome 1
Adipose most abundant gene transcript 1
Apolipoprotein A-II
Apolipoprotein A-IV
Apolipoprotein B (including Ag (x) antigen)
Apolipoprotein C1
Apolipoprotein D
Apolipoprotein E
Agouti (mouse)-signaling protein
ATPase, Na⫹/K⫹ transporting, alpha 2 (⫹) polypeptide
ATPase, Na⫹/K⫹ transporting, beta 1 polypeptide
Attractin (with dipeptidylpeptidase IV activity)
12q24.1
4p16.3
2p25
20q12-q13.11
10q24-q26
5q31-q32
10q24-q26
2p13-q13
8p12-p11.2
9q34.3
16q22
15q11-q13
1q42-q43
16q13-q21
20q13.2
15q
9q34.1
2p13-p12
3q27
1q21-q23
11q23
2p24-p23
19q13.2
3q26.2-qter
19q13.2
20q11.2-q12
1q21-q23
1q22-q25
20p13
C
BATF
BBS1
BBS2
BBS3
BBS4
BBS5
BBS6
BF
BFLS
BRS3
BSCL1
BSCL2
C3
CAPN10
CART
Regulator of transcription factor B-ZIP
Bardet-Biedl syndrome 1
Bardet-Biedl syndrome 2
Bardet-Biedl syndrome 3
Bardet-Biedl syndrome 4
Bardet-Biedl syndrome 5
Bardet-Biedl syndrome 6
B-factor, properdin
Borjeson-Forssman-Lehman syndrome
Bombesin receptor 3
Berardinelli-Seip Congenital Lipodystrophy
Berardinelli-Seip Congenital Lipodystrophy
Acylation-stimulating protein
Calpain 10
Cocaine—amphetamine-regulated transcript
14q24.3
11q13
16q21
3p13-p12
15q22.3-q23
2q31
20p12
6p21.3
Xq26.3
Xq26-q28
9q34
11q13
19p13.3
2q37.3
5q
A
B
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Gene or locus
CBFA2T1
CCKAR
CCKBR
CDGS1A
CD36L1
CEBPA
CEBPB
CHOD
CHRM3
COH1
COL8A2
CPE
CPHD
CYP7A1
CYP19
D
F
DGAT1
DRD1
DRD2
EIF4EBP1
ESD
ESR1
FABP2
FABP4
FBS
FGFR3
FGF13
FIZZ3
FPLD
FSH-R
G
H
GCGR
GCK
GH1
GHRH
GHRHR
GHRL
GLO1
GNAS1
GNB3
GPC3
GPC4
364
Name
Location
Core-binding factor, runt domain, alpha subunit 2; translocated to,
1; cyclin D-related
Cholecystokinin A receptor
Cholecystokinin B receptor
Carbohydrate-deficient glycoprotein syndrome type Ia
CD36 antigen (collagen type I receptor, thrombospondin receptor)like 1
CCAAT enhancer binding protein
CCAAT enhancer binding protein
Choroideremia with deafness
Muscarinic receptor M3
Cohen syndrome 1
Collagen, type VIII, alpha 2
Carboxypeptidase E
Combined Pituitary Hormone Deficiency
Cytochrome P450, subfamily VIIA (cholesterol 7 alphamonooxygenase), polypeptide 1
Transferase Aromatase
8q22
Acyl CoA: diacylglycerol acyl transferase
Dopamine receptor D1
Dopamine receptor D2
Eukaryotic translation initiation factor 4E binding protein 1
Esterase D/formylglutathione hydrolase
Estrogen receptor 1
Fatty acid binding protein 2, intestinal
Fatty acid binding protein 4
Fanconi-Bickel syndrome
Fibroblast growth factor receptor 3 (achondroplasia, thanatophonic
dwarfism)
Fibroblast Growth Factor 13
Found in inflammatory zone 3 (resistin)
Familial Partial Lipodystrophy Dunnigan
Follicular stimulating hormone receptor
8q-ter
5q34-q35
11q23
8p12
13q14.1-q14.2
6q25.1
4q28-q31
8q21
3q26.1-q26.3
4p16.3
Glucagon receptor
Glucokinase (hexokinase 4, maturity onset diabetes of the young 2)
Growth hormone
Growth hormone releasing hormone
Growth hormone releasing hormone receptor
Ghrelin
Glyoxalase I
Guanine nucleotide binding protein (G protein), alpha stimulating
activity polypeptide 1
Guanine nucleotide binding protein (G protein), beta polypeptide 3
Glypican 3
Glypican 4
17q25
7p15.3-p15.1
17q24.1
20q11.2
7p14
3p26-p25
6p21.3-p21.1
20q13.2-q13.3
OBESITY RESEARCH Vol. 11 No. 3 March 2003
4p15.2-p15.1
11p15.4
16p13
12q24.1-q24.3
19q13.11
20q12-q13.1
Xq21.1-q21.2
1q41-q44
8q22-q23
1p34.3-p32.3
4q32
5q
8q11-q12
15q21
Xq26
19p13.3
1q21-q22
2p21-p16
12p13
Xq26.1
Xq26.1
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Gene or locus
Name
Location
12q13.2
5q31-q32
4q28.2-q31.1
19q13.3
17q21
4p16.3
12q15
3p25
6p21.3
1p13.1
HSD11B1
HTR1B
HTR2A
HTR2C
␣-Glycerol phosphate dehydrogenase
Glucocorticoid receptor
Glycophorin A (includes MN blood group)
Glycogen synthase 1 (muscle)
Hypocretin (Orexin)
Huntingtin
Component enhancesome Hmgic
Histamine receptor H1
Heat-shock 70-kD protein 1B
Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid deltaisomerase 1
Hydroxysteroid (11-beta) dehydrogenase 1
5-hydroxytryptamine (serotonin) receptor 1B
5-hydroxytryptamine (serotonin) receptor 2A
5-hydroxytryptamine (serotonin) receptor 2C
K
ICAM-1
IGF1
IGF1R
IGF2
IGHD
IGKC
ILIRN
INS
INSR
IPW
IRS
IRS1
ISL1
KEL
Intercellular adhesion molecule 1
Insulin-like growth factor 1 (somatomedin C)
Insulin-like growth factor 1 receptor
Insulin-like growth factor 2 (somatomedin A)
Isolated growth hormone deficiency
Immunoglobulin ␬ constant
Interleukin 1 receptor antagonist
Insulin
Insulin receptor
Imprinted in Prader-Willi syndrome
Insulin resistance syndromes
Insulin receptor substrate 1
ISL1 transcription factor, LIM/homeodomain (islet-1)
Kell blood group
19p13.2
12q22-q23
15q25-q26
11p15.5
7p15-p14
2p12
2q14.2
11p15.5
19p13.3-p13.2
15q11-q12
19p13.3
2q36
5q22.3
7q33
LDLR
LEPR
LEP
LIPE
LMNA
LPIN1
LPL
Low density lipoprotein receptor (familial hypercholesterolemia
Leptin receptor
Leptin (murine obesity homolog)
Lipase, hormone sensitive
Lamin A/C
Lipin
Lipoprotein lipase
19p13.3
1p31
7q31.3
19q13.1-q13.2
1q21.2-q21.3
2p21
8p22
MAGE-like 2
Melanocortin 3 receptor
Melanocortin 4 receptor
Melanocortin 5 receptor
Mental retardation, epileptic seizures, hypogonadism and genitalism,
microcephaly and obesity syndrome
McKusick-Kaufman syndrome
15q11-q12
20q13.2-q13.3
18q22
18p11.2
Xq22.13-p21.1
GPD1
GRL
GYPA
GYS1
HCRT
HD
HMGA2
HRH1
HSPA1B
HSD3B1
I
1q32-q41
6q13
13q14-q21
Xq24
L
M
N O
MAGEL2
MC3R
MC4R
MC5R
MEHMO
MKKS
20p12
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Gene or locus
MRXS7
MRXS11
MT1A
MT1B
MYO9A
NDN
NHLH2
NPY
NPY5R
NR0B2
ORM1
P
S
P1
PCSK1
PGD
PHF6
PLIN
PMCH
PMM2
POMC
PON2
PPARA
PPARG
PPARGC1
PPCD
PPY
PROP1
PRKAB2
PTPN1
PTPRB
PWCR1
PWS
SAH
SDC1
SERPINE1
SGBS1
SGBS2
SH3D5
SIM1
SLC2A2
SLC6A1
SNRPN
SREBP-1C/1A
366
Name
Location
Mental retardation, X-linked, syndromic 7
Mental retardation, X-linked, syndromic 11
Metallothionein I
Metallothionein II
Myosin IXA
Necdin (mouse) homolog
Neural transcription factor 2
Neuropeptide Y
Neuropeptide Y receptor Y5
Nuclear receptor subfamily 0, group B, member 2
Orosomucoid 1
Xp11.3-q22.1
Xq26-q27
16q13
16q13
15q22-q23
15q11.2-q12
1p12-p11
7p15.1
4q31-q32
1p36.1
9q31-q32
P blood group (P one antigen)
Proprotein convertase subtilisin/kexin type 1
Phosphogluconate dehydrogenase
PHD finger protein 6
Perilipin
Melanin concentrating hormone
Phosphomannomutase 2
Proopiomelanocortin
Paraoxonase 2
Peroxisome proliferative activated receptor, alpha
Peroxisome proliferative activated receptor, gamma
Peroxisome proliferative activated receptor, gamma, coactivator 1
Posterior Polymorphous Corneal dystrophy
Pancreatic polypeptide
Prophet of Pit 1, paired-like homeodomain transcription factor
Protein kinase A RII␤
Protein tyrosine phosphatase, non-receptor type 1
Protein tyrosine phosphatase 1 B
Prader-Willi syndrome chromosome region 1
Prader-Willi syndrome
Prader-Willi-like Syndrome
Prader-Willi-like Syndrome
Shashi X-linked Mental Retardation Syndrome
SA hypertension-associated homolog (rat)
Syndecan 1
Serine (or cysteine) proteinase inhibitor, clade E (nexin,
plasminogen activator inhibitor type 1), member 1
Simpson-Golabi-Behmel syndrome 1
Simpson-Golabi-Behmel syndrome 2
SH3-domain protein 5 (ponsin)
Single-minded (Drosophila) homolog 1
Solute carrier family 2 (facilitated glucose transporter), member 2
Gamma-aminobutyric acid transporter 1
Small nuclear ribonucleoprotein polypeptide N
Sterol regulatory element binding protein
22q11.2-qter
5q15-q21
1p36.2-p36.13
Xq26.3
15q26
12q23-q24
16p13.3-p13.2
2p23.3
7q21.3
22q12-q13.1
3p25
4p15.1
20q11
17q21
5q
1q12
20q13.1-q13.2
12q15-q21
15q11.2
15q11-q13
6q1
Xq23-q25
Xq26-q27
16p13.11
2p24.1
7q21.3-q22
OBESITY RESEARCH Vol. 11 No. 3 March 2003
Xq26
Xp22
10q23.3-q24.1
6q16.3-q21
3q26.1-q26.2
3p25-p24
15q12
17p11.2
The Human Obesity Gene Map: The 2002 Update, Chagnon et al.
Gene or locus
STAT5A
SUR1
T
U W
TBX3
TCF8
TGFB1
TH
THRB
THRS
TNF
TNFRSF1B
TNRC11
TUB
UCP1
UCP2
UCP3
UMS
VDR
VGF
WTS
ZNF127
(MKRN3)
Name
Location
Signal transducer and activator of transcription 5
Sulfonylurea receptor 1
17q11.2
11p15.1
T-box3 (ulnar mammary syndrome)
Transcription factor 8 (represses interleukin 2 expression)
Transforming growth factor, beta 1
Tyrosine hydroxylase
Thyroid hormone receptor, beta
Thyroid Hormone Resistance syndrome
Tumor necrosis factor
Tumor necrosis factor receptor superfamily member 1B
Trinucleotide-repeat-containing gene 11 (THR-associated protein,
230-kDa subunit)
Tubby (mouse) homolog
Uncoupling protein 1 (mitochondrial, proton carrier)
Uncoupling protein 2 (mitochondrial, proton carrier)
Uncoupling protein 3 (mitochondrial, proton carrier)
Ulnar-Mammary syndrome Schinzel syndrome
Vitamin D (1,25-dihydroxyvitamin D3) receptor
Neural expressed protein
Wilson-Turner X-linked mental retardation syndrome
Makorin, ring finger protein, 3
12q24.1
10p11.2
19q13.1
11p15.5
3p24.3
3p24.3
6p21.3
1p36.3-p36.2
Xq13
11p15.5
4q28-q31
11q13
11q13
12q23-q24.1
12q12-q14
7q22
Xp21.2-q22
15q11-q13
* The gene symbols, names and cytogenetic locations are from the Locus Link Web site (http://www.ncbi.nlm.nih.gov/LocusLink) available
from NCBI, which provides the official nomenclature of genetic loci. For the abbreviations of the Mendelian disorders (see Table 3). For
the Mendelian disorders, the localization is from the OMIM data base.
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