Confirmed Locus on Chromosome 11p and Candidate Loci
on 6q and 8p for the Triglyceride and Cholesterol Traits of
Combined Hyperlipidemia
Rossitza P. Naoumova, Stephanie A. Bonney, Sophie Eichenbaum-Voline, Hetal N. Patel,
Bethan Jones, Emma L. Jones, Joanna Amey, Susan Colilla, Clare K.Y. Neuwirth, Rebecca Allotey,
Mary Seed, D. John Betteridge, David J. Galton, Nancy J. Cox, Graeme I. Bell,
James Scott, Carol C. Shoulders
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Background—Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile
and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and
triglyceride or either lipid alone) is unknown.
Methods and Results—We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and
performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities.
Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, and 11p14.1-q12.1 produced evidence for linkage to FCHL.
Chromosomes 6 and 8 are newly identified candidate loci that may respectively contribute to the triglyceride (logarithm
of odds [LOD], 1.43; P⫽0.005) and cholesterol (LOD, 2.2; P⫽0.0007) components of this condition. The data for
chromosome 11 readily fulfil the guidelines required for a confirmed linkage. The causative alleles may contribute to
the inheritance of the cholesterol (LOD, 2.04 at 35.2 cM; P⫽0.0011) component of FCHL as well as the triglyceride
trait (LOD, 2.7 at 48.7 cM; P⫽0.0002).
Conclusions—Genetic analyses identify 2 potentially new loci for FCHL and provide important positional information for
cloning the genes within the chromosome 11p14.1-q12.1 interval that contributes to the lipid abnormalities of this highly
atherogenic disorder. (Arterioscler Thromb Vasc Biol. 2003;23:2070-2077.)
Key Words: combined hyperlipidemia 䡲 lipid abnormalities 䡲 complex genetic disorder
䡲 chromosome 11p14.1-q12.1 䡲 metabolic syndrome
C
offspring of affected family members were hyperlipidemic.
However, subsequent segregation analyses4 – 8 and 2 genomewide studies9,10 have suggested a more complex inheritance
pattern.
The etiology of the mixed hyperlipidemia (increases in
both cholesterol and triglyceride or in either lipid alone) in
FCHL is unknown.4,6,10 –12 Stable isotope studies have established a correlation between increased serum triglyceride
levels and the production of VLDL and apolipoprotein (apo)
B.13,14 FCHL has also been associated with defective catabolism of VLDL and chylomicrons15,16 and increased production of apoCIII and insulin resistance.17–24 The mixed lipid
profile of FCHL may also occur in patients with the metabolic syndrome,25 which comprises 3 or more metabolic
ombined hyperlipidemia (raised cholesterol and triglyceride levels) affects 1% to 2% of individuals in Western
societies. The term familial combined hyperlipidemia
(FCHL) was coined by Goldstein et al1 to describe a pattern
of lipid abnormalities in 47 Seattle pedigrees, which was
simultaneously observed by others in other families.2,3 FCHL
was originally considered a dominant disorder with incomplete penetrance until the third decade that primarily affected
blood triglyceride levels, with a secondary effect on cholesterol levels.1 This mode of transmission was based on the
pattern of serum cholesterol and triglyceride levels in the
original Seattle families. The distribution of triglyceride
levels in the first-degree relatives of affected probands above
the age of 20 years was bimodal, and less than one half of the
Received August 20, 2003; revision accepted August 21, 2003.
From the Genomic and Molecular Medicine Group (R.P.N., S.A.B., S.E.-V., H.N.P., B.J., E.L.J., J.A., C.K.Y.N., C.C.S.), Medical Research Council
Clinical Sciences Centre, Hammersmith Hospital; Department of Cardiovascular Medicine (M.S.), Charing Cross Hospital; and Genetics and Genomics
Research Institute (J.S.), Imperial College London, UK; Departments of Medicine and Human Genetics (S.C., N.J.C., G.I.B.) and Biochemistry and
Molecular Biology (G.I.B.), Howard Hughes Medical Institute, University of Chicago, Ill; Department of Medicine (D.J.B.), Royal Free and University
College Medical School, University College London, UK; and Departments of Diabetes and Metabolic Medicine (R.A.) and Human Metabolism and
Genetics (D.J.G.), St Bartholomew’s Hospital, London, UK.
Consulting Editor for this article was Goran Hansson, Karolinska Institute, Stockholm, Sweden.
Correspondence to Dr Carol C. Shoulders or Professor James Scott, Genomic and Molecular Medicine Group, MRC Clinical Sciences Centre, Imperial
College London, DuCane Rd, London W12 0NN, UK. E-mail [email protected] or [email protected]
© 2003 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
2070
DOI: 10.1161/01.ATV.0000095975.35247.9F
Naoumova et al
TABLE 1.
Confirmed and Candidate Loci for FCHL
2071
Description of Probands and Spouses
First Cohort
Second Cohort
Probands
Spouses
Probands
Spouses
Male
Female
Male
Female
Male
Female
Male
Female
Age, y
50.5⫾13.1
61.9⫾12.7
56.5⫾13.9
50.5⫾10.0
48.9⫾9.9
55.6⫾7.4
58.1⫾7.7
54.6⫾7.5
Body mass index, kg/m2
24.0⫾7.1
23.1⫾7.0
25.0⫾3.0
24.1⫾3.5
26.6⫾2.5
26.1⫾3.0
26.0⫾3.8
24.7⫾3.7
Serum Cholesterol, mg/dL
312.7⫾34.7
355.1⫾54.0
212.6⫾137.0
231.6⫾112.0
316.5⫾54.0
320.4⫾77.2
232.7⫾45.5
225.6⫾34.5
Serum Triglyceride, mg/dL
415.9⫾159.3
477.9⫾380.5
137.0⫾83.5
112.0⫾67.2
433.6⫾256.6
345.1⫾150.4
114.3⫾60.0
124.6⫾49.2
Values are mean⫾SD.
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abnormalities, including hypertriglyceridemia, decreased
HDL cholesterol, insulin resistance, hypertension, and abdominal obesity. FCHL and the metabolic syndrome contribute to premature coronary heart disease (CHD) in up to 40%
of patients.26 –30
In this study, we present an affected sibling and relative
pair linkage analysis that identifies chromosomes 6q16.1q16.3 and 8p23.3-p22 as potential FCHL loci and quantitative
trait linkage analyses that suggest that these loci may respectively affect the triglyceride and cholesterol components of
this condition. More importantly, we provide independent
replication for an FCHL-susceptibility locus on chromosome
11p14.1-q12.19 that affects the triglyceride component of this
condition. This interval may also contain a separate quantitative trait locus (QTL) for serum cholesterol levels, giving
support to the data of Klos et al.31
Methods
Families
Two cohorts of extended, multigenerational families were assembled. The first comprised 45 families and was assembled between
1988 and 1992 through white British probands attending tertiary
referral specialized lipid clinics at Northwick Park Hospital and the
Hammersmith Hospital, London, UK. The second, comprising 113
pedigrees, was assembled between 1998 and 2001 through probands
attending clinics at Hammersmith Hospital, Charing Cross Hospital,
University College London Hospital, and Saint Bartholmews Hospital in London, UK. Based on previous FCHL1,6,9,10,12 studies and
PROCAM,28 probands had cholesterol and triglyceride levels greater
than age- and sex-specific 95th and 90th percentile values, respectively, and a blood relative with raised plasma cholesterol or
triglyceride or both greater than age- and sex-specific 90th percentile
values. In the absence of British values, the Lipid Research Clinic’s32
percentile points were used. In this data set, 90th and 95th percentile
cut-off values for cholesterol levels for men between 40 to 65 years
of age range from 247.4 to 259.1 mg/dL and 265.2 to 274.1 mg/dL,
respectively. 90th percentile values for triglyceride levels range from
248.7 to 254.0 mg/dL. In PROCAM (4599 North European men
between 40 and 65 years of age), median cholesterol levels were
251.8⫾47.3 and 222.9⫾41.0 mg/dL for participants with and without CHD, respectively. Median triglyceride levels were 163.0 and
134.5 mg/dL. In the Lipid Research Clinic’s data set, 75th percentile
cut-off values for the same age group are 170.8 to 180.5 mg/dL.
Exclusion criteria for participants were age ⬍16 years and other
forms of genetic hyperlipidemia (eg, familial hypercholesterolemia)
based on molecular diagnosis, standard clinical signs, or diagnostic
criteria. Patients with secondary hyperlipidemia (eg, body mass
index ⬎30 kg/m2, diabetes mellitus, hypothyroidism, liver and
kidney disease, alcohol abuse, or medication influencing lipid
metabolism) were also excluded. Ethical committees of all centers
approved the study design, and participants gave written informed
consent. Fasting levels of total cholesterol, triglycerides, and HDL
cholesterol were determined by automated methods using commercial kits and interassay controls. Serum apoB (second cohort only)
was measured using an automated immunoturbidimetric assay
(Beckman Instruments, Inc). LDL cholesterol levels were calculated
from the standard formula, as follows: LDL cholesterol (mg/dL)
⫽total cholesterol⫺[HDL cholesterol⫹(triglyceride/5)]. Phenotyping of
all individuals was based on lipid levels before the administration of
lipid-lowering medication.
Genotyping
The primary screen was performed using the version 9A Weber
screening set of microsatellite markers and 45 families, the core of
which has been described.6 Follow-up studies were performed in 3
stages as cohort 2 families were assembled and included all family
members irrespective of affection status. Fifteen loci (1 to 15),
1q23.3, 2p25.1, 2q32.1-q33.3, 3q24, 4q21.23-q23, 4q35.1, 7q34q36.2, 9p21.1, 9q21.13-q21.32, 12q24.33, 13q22.3-q31.1, 17p11.2q11.2, 20p12.2-p12.1, 20q12.1-q13.12, and 21q21.1-q21.2, were
evaluated in the first 56 families of cohort 2. In the absence of any
evidence for linkage to an FCHL-dichotomised trait (logarithm of
odds [LOD] ⬍0.1), these loci were pursued no further. Nine
additional loci (16 to 24), 3p21.31-p14.2, 4p16.2-p16.1, 5q34-q35.1,
7p12.1, 8q24.21, 10q26.3, 14q11.2-q12, 15q26.2-q26.3, and
20p11.22, were evaluated in families 1 to 78 of cohort 2. Five loci
(25 to 29), 2q35-q36.3, 6q16.1-q16.3, 8p23.3-p22, 10p11.22-q21.1,
and 11p14.1-q12.1, produced nominal evidence for linkage to an
FCHL-dichotomised trait in the second-stage analysis and were
therefore examined in an additional 35 families. Marker details are
presented in Table I, available online at http://atvb.ahajournals.org.
Linkage Analysis
Linkages results have been deposited on our website (http://www.
csc.mrc.ac.uk/ResearchGroups/GenomicAndMolecularMedicine/
Home/home.html). Multipoint and 2-point dichotomised trait analyses were conducted with GENEHUNTER-PLUS33 and GENEHUNTER, respectively. Estimates of allele sharing were based on
marker allele frequencies in pedigree founders. The Gaussian distribution was used to approximate the distribution of the NPL⫹ statistic
and nominal probability values. Two-point parametric heterogeneity
LODs (HLODs) were computed on data from all family members
(ie, including all unaffected individuals) using a dominant model and
penetrances of 40% and 90% for carriers with 1 and 2 copies of the
disease allele, respectively. The disease allele frequency was set at
0.03, and phenocopies at a frequency of 0.001. This heterogeneity
model was used to allow for the possibility that a subset of our
families had a significantly higher reoccurrence risk of FCHL and a
lower rate of phenocopies than the average reoccurrence risk
observed in the total data set (Table 2).
Quantitative trait linkage analysis was performed with SOLAR34
and MERLIN-REGRESS,35 implemented in Merlin version 0.9.1.
For SOLAR, we first removed variation in traits attributable to the
covariates, body mass index, age, and sex (as well as their interactions) and then performed 2-point and multipoint linkage analyses.
The ascertainment correction option was used for probands only.
Estimates for the proportion of variance attributable to covariates
were 18.27% for log (triglyceride), 24.65% for log (total cholester-
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Arterioscler Thromb Vasc Biol.
November 2003
ol), and 25.29% for apoB. Log transformation of lipid parameters
was performed before the covariate fitting exercise to normalize
distributions. Linkage was evaluated by comparing the likelihood of
a variance component model that permits a given marker locus
(assumed to be tightly linked to a locus influencing the quantitative
trait) to account for some of the additive genetic variance to the
likelihood of a purely polygenic model. The difference between the
two log10 likelihood produces a LOD equivalent to the classical LOD
of linkage analysis.36 For MERLIN-REGRESS, the analysis was
performed without removing the effects of covariates. The independent variables were defined as trait values and identity by descent
alleles as dependent variables because regression coefficient estimates are not biased by sample selection through independent
values.35 Cholesterol and triglyceride levels were logged to normalize distributions. Population trait means and variances were computed from the spouses within the families.
Results
Genome-Wide Screen and Identification of
Candidate Loci
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To evaluate the genetic basis for the lipid abnormalities of
FCHL, we screened the human genome of 503 individuals
from 45 extended pedigrees (Table 1) with markers at an
average map density of 10 cM and evaluated the data using
standard and correlated diagnostic criteria for affected status.
These were (1) triglyceride trait, triglyceride ⱖ90th percentile age- and sex-specific values; (2) combined hyperlipidemia phenotype, raised cholesterol and triglyceride levels and
ⱖ90th percentile age- and sex-specific values; (3) cholesterol
trait, cholesterol ⱖ90th percentile age- and sex-specific
values; and (4) 95th percentile FCHL lipid trait, cholesterol or
triglyceride level ⱖ95th percentile age- and sex-specific
values. The fourth category was designed to ensure all
individuals with a probable genetic cause for hyperlipidemia
were included. The number of affected relative pairs in the
pedigrees ranged from 77 for the combined hyperlipidemia
phenotype to 345 for the cholesterol trait (Table 2). Sibling
reoccurrence risk (␭s) values ranged from 2.5 for the 95th
percentile FCHL lipid trait to 3.5 for the combined hyperlipidemia phenotype (Table 2).
The analysis of FCHL as a dichotomous trait is consistent
with the analysis of Aouizerat et al9 and Pajukanta et al.10
Fifteen genomic regions produced LODs ⬎0.9 (P⬍0.022) for
a FCHL-related lipid trait (Table 3; Figure I, available online
at http://atvb.ahajournal.org), and of these, 3 were coincident
with regions previously implicated in FCHL (Table 3). All 15
regions were followed up in our second cohort of families,
which was recruited by the same strategy as cohort 1 families.
The 2 cohorts of families were comparable in most respects,
including the proportion of male and female individuals
affected with each phenotype and the number of affected
sibling and relative pairs per family (Tables 1 and 2).
However, subtle differences were observed between the
distributions of lipid abnormalities, which required us to keep
the initial analyses of cohort 2 separate from cohort 1. Cohort
2 contained a higher proportion of affected sibling and
relative pairs with the combined hyperlipidemia or triglyceride trait compared with the families in cohort 1 (P⬍0.001
level). In addition, ␭s values were slightly higher (Table 2) in
the second cohort, suggesting that familial factors may have
played a more important role in determining lipid levels in
TABLE 2.
Breakdown of Data Sets
Breakdown of Sample
First Cohort
Second Cohort
No. of probands, M/F
29/16
86/27
271/232
651/617
Combined hyperlipidemia*
46/25
117/75
Triglyceride trait†
61/36
156/109
Total No. of subjects, M/F
No. of affected subjects, M/F
Cholesterol trait‡
111/85
232/163
95th FCHL lipid trait§
111/85
213/156
Affected sibling pairs/relative
pairs
Combined hyperlipidemia
36/77
86/177
Triglyceride trait
51/110
131/270
Cholesterol trait
130/345
219/561
95th FCHL lipid trait
114/324
201/480
Sibling reoccurrence risk
CI95储
CI95
Combined hyperlipidemia
3.5 关1.75 to 7.13兴¶
5.4 关3.19 to 9.13兴**
Triglyceride trait
2.6 关1.50 to 4.53兴#
3.8 关2.50 to 5.60兴**
Cholesterol trait
2.6 关1.88 to 3.69兴**
3.2 关2.37 to 4.25兴**
95th FCHL lipid trait
2.5 关1.68 to 3.57兴††
4.5 关3.19 to 6.22兴**
*Combined hyperlipidemia⫽cholesterol and triglyceride levels ⱖ agespecific 90th percentile values.
†Triglyceride level ⱖ age-specific 90th percentile values.
‡Cholesterol level ⱖ age-specific 90th percentile values.
§Cholesterol or triglyceride level ⱖ age-sex-specific 95th percentile values.
储CI95⫽95th percentile Confidence Interval.
¶P⫽4.2⫻10⫺4; #P⫽6.7⫻10⫺4; **P⬍1⫻10⫺7; ††P⫽3⫻10⫺6.
these families. The differences between cohort 1 and 2 may
additionally relate to changes in lifestyle factors that have
occurred in the interval between the recruitment of the
families in these 2 cohorts.
The analysis of cohort 2 provided support for 2, 6q16.1q16.3 (Figure, panel A) and 8p23.3-p22 (Figure, panel B), of
the 15 chromosomal regions that had produced evidence for
linkage to a FCHL dichotomised trait in the genome-wide
screen of cohort 1 (Figure I, Table 1).
Second-Stage Analyses of Chromosome
6q16.1-q16.3 and 8p23.3-p22
The support for linkage of the chromosome 6q16.1-q16.3
interval to a FCHL-related trait in our second cohort of
families was modest but present in all data sets. In the
dichotomised trait analyses, the highest nonparametric multipoint LOD (LOD, 0.64; NPL⫹, 1.72; P⫽0.043) was obtained for the 95th percentile FCHL lipid trait, near marker
D6S1671 at 105.7 cM (Figure, panel A). In the combined data
set (ie, cohorts 1 and 2), the LOD increased to 0.79 (NPL⫹,
1.90; P⫽0.028) at 107.9 cM (Figure, panel B), attributable to
a positive LOD in 49.3% of families with an affected sibling
or relative pair with this trait.
In the combined data sets, the highest multipoint LODs for
the triglyceride trait combined hyperlipidemia phenotype and
cholesterol trait were, respectively, 0.88 (P⫽0.022) at 107.9
cM, 0.99 (P⫽0.016) at 99.4 cM, and 0.03 at 97.1 cM (Figure,
panel A; Table II, available online at http://atvb.ahajournals.org),
suggesting that the candidate linkage of chromosome 6q16.1-
Naoumova et al
Confirmed and Candidate Loci for FCHL
2073
TABLE 3. Loci With Nominal Evidence of Linkage in Primary
Genome–Wide Screen
Chromosome*
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Phenotype
cM
Marker
NPL/LOD
P
2q35–36.3
CHL†
223.0
D2S1363
2.16/1.01
0.015
3p21.31–14.2
CHL
69.0
D3S2409
2.10/0.96
0.018
3q24
CHL
162
D3S1744
2.02/0.89
0.022
4p16.2–16.1
TG‡
0
D4S2366
2.19/1.04
0.014
4p16.2–16.1
CHL
2.6
D4S2366
2.34/1.19
0.010
4q21.23–23
95th FCHL lipid§
93.8
D4S2361
2.52/1.38
0.006
4q21.23–23
TC储
93.8
D4S2361¶
2.29/1.15
0.011
4q35.1
TG
193.4
D4S408
2.68/1.56
0.004
6q16.1–16.3
CHL
102.0
D6S1056
2.14/0.99
0.016
6q16.1–16.3
TG
102.0
D6S1056
2.10/0.95
0.018
6q16.1–16.3
95th FCHL lipid
108.0
D6S1021
2.11/0.97
0.017
7q34–36.2
CHL
155.4
D7S2195
2.19/1.04
0.014
8p23.3-p22
95th FCHL lipid
0
D8S264
2.20/1.05
0.014
8p23.3-p22
CHL
26.0
D8S1106
2.10/0.96
0.018
9p21.1
TG
52.0
D9S1118
2.34/1.19
0.010
9q21.13–21.32
TG
75.0
D9S1122#
2.49/1.34
0.006
17p11.2-q11.2
CHL
47.6
D17S2196
2.20/1.05
0.014
20p12.2–12.1
CHL
31.0
D20S604
2.31/1.16
0.010
20p12.2–12.1
TG
32.2
D20S604
2.71/1.59
0.003
20p11.22
TG
47.8
D20S477
2.61/1.48
0.005
20q12.1–13.12
TG
56.8
D20S478**
2.60/1.47
0.005
*Cytogenetic locations encompass markers used in the follow-up studies (online Table I).
†CHL indicates combined hyperlipidemia, cholesterol and triglyceride level ⱖ age- and sexspecific 90th percentile values.
‡TG indicates triglyceride level ⱖ age- and sex-specific 90th percentile values.
§Cholesterol or triglyceride level ⱖ age- and sex-specific 95th percentile values.
储Cholesterol ⱖ age- and sex-specific 90th percentile values.
¶A parametric LOD score of 0.94 was obtained with this marker for TC trait of FCHL.10
#A parametric LOD score of 0.81 was obtained with this marker TG trait of FCHL.10
**D20S481 at 62.3cM produced a parametric LOD score of 0.91 for the TG trait of FCHL.10
q16.3 interval for FCHL might be attributable to the triglyceride
component of this condition. This was supported by 2-point
parametric and quantitative linkage analyses. In 2-point analyses, the highest HLODs were 0.71 (␣⫽0.30) for the triglyceride
trait in cohort 1 with marker D6S1021 at 112.2.cM, compared
with 1.91 (␣⫽0.25) in cohort 2 with marker D6S1671 at 107.9
cM (Table III, available online at http://atvb.ahajournals.org). A
candidate QTL for serum triglyceride at 107.9 cM was also
detected by the quantitative trait linkage analyses, implemented
in SOLAR. Two-point and multipoint LODs were 1.8 (Table IV,
available online at http://atvb.ahajournals.org) and 1.43
(P⫽0.005), respectively. (Figure, panel A). The corresponding
values in MERLIN-REGRESS were more modest, but as in the
SOLAR, we obtained the highest LODs for a triglyceride QTL
(Tables V and VI, available online at http://atvb.ahajournals.org).
To evaluate the 8p23.3-p22 chromosomal region in our
second cohort of families, we used 9 markers spanning a
41-cM interval (Figure, panel B). In the dichotomised trait
analyses, the highest nonparametric multipoint LOD (LOD,
1.76; NPL⫹, 2.85; P⫽0.0022) was obtained at 28.8 cM for the
95th percentile FCHL lipid trait (Figure, panel B). This was
attributable to a positive LOD in 47.8% of affected families.
Combining the data with cohort 1 families shifted the peak
LOD (LOD, 1.80; NPL⫹, 2.87; P⫽0.0022) to 11.1 cM, which
coincided with the smaller of the 2 peaks in the cohort 2
families (Figure, panel B). This genomic region also produced the highest LODs for a candidate QTL for serum
cholesterol (LOD, 2.20 at 8.3 cM; P⫽0.0007) and triglyceride (LOD, 1.69 at 0.73 cM; P⫽0.003) (Figure, panel B; Table
VI, available online at http://atvb.ahajournals.org).
Two-point parametric analyses produced some support for
linkage of the chromosome 8p23.3-p22 interval to a FCHLrelated trait. Cohort 1 produced a HLOD of 1.64 (␣⫽0.62) for
the combined hyperlipidemia trait with markers D8S1106 at
26.4 cM (data available on our website). Cohort 2 produced
HLODs of 1.27 (␣ 0.26) and 1.69 (␣⫽0.55) with markers
D8S1721 and D8S549 at 17.0 and 31.7 cM, respectively, for
the 95th percentile FCHL lipid trait (online Table III).
Replication of the Chromosome
11p14.1-q12.1 Linkage
We also examined 14 chromosomal regions (1q23.3, 2p25.1,
2q32.1-32.3, 5q34-35.1, 7p12.1, 8q24.21, 10p11.22-10q21.1,
10q26.3, 11p14.1-q12.1, 12q24.33, 13q22.33-31.1, 14q11.212, 15q26.1-26.3, 21q21.1-21.2) that had produced evidence
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Arterioscler Thromb Vasc Biol.
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of linkage to FCHL in a previous genome-wide scan9,10 but
no such evidence in our primary genome-wide screen of 45
white British families (Figure I). Follow-up studies, performed in our second cohort of families, produced multipoint
LODs ⬎0.5 for 2 of these 14 chromosomal loci.
The first locus, 10p11.22-10q21.1, produced a multipoint
LOD of 0.82 (P⫽0.026) at 68.8 cM for triglyceride as a
dichotomised trait (data available on our website), providing
some support for linkage of this locus to the triglyceride trait
of FCHL.10 In our combined data set, the highest multipoint
LOD was more modest, 0.55 at 70.23 cM (Table II). Modest
LODs were also attained when we analyzed the locus as a
serum triglyceride QTL. The highest 2-point LODs were 1.40
(SOLAR) and 0.80 (MERLIN-REGRESS) at 75.6 cM (Tables IV and V), compared with multipoint LODs of 0.95 (data
available on our website) and 0.67 (Table VI).
The second locus, 11p14.1-q12.1, was evaluated in our
second cohort of families using 9 markers spanning a 40-cM
interval (ie, 21.5 to 61.8 cM). The highest LODs were
obtained for the triglyceride trait of FCHL in all analyses
(Figure, panel C, Table 4, and Tables II through VI). The
dichotomised trait analyses produced a multipoint nonparametric LOD of 2.9 (NPL⫹, 3.63; P⫽0.00014) at 48.9 cM
(Figure, panel C) compared with a 2-point parametric HLOD
of 3.05 (␣⫽0.37) at 47.1 cM (Table III). In the combined data
set, the highest multipoint LOD was 2.25 (NPL⫹, 3.22;
P⫽0.0007) at 49.9 cM (Figure, panel C). This LOD derived
from 48.7% of families with an affected sibling or relative
pair with the triglyceride trait of FCHL.
In quantitative analyses, MERLIN-REGRESS produced
the highest multipoint LOD (LOD, 2.7; P⫽0.0002) at 48.7
cM, whereas the SOLAR analyses produced the highest
signal (LOD, 2.7; P⫽0.0002) at 58.4 cM (Figure, panel C).
MERLIN-REGRESS additionally detected a candidate QTL
(LOD, 2.04; P⫽0.0011) for cholesterol (Figure, panel C),
consistent with the data of Klos et al.31 We conclude that the
data for chromosome 11 combined with previous data9,31
readily fulfil the standard criteria proposed for a confirmed
linkage37 and indicate that the underlying sequence variant
may contribute to the cholesterol component of FCHL as well
as the triglyceride trait of this condition.
Discussion
Multipoint plots for chromosomes 6 (A), 8 (B), and 11 (C). LODs
for dichotomised traits derive from the analysis of 45 (first
cohort), 113 (second cohort), and 158 (combined) FCHL pedigrees with the Genehunter-Plus (GH-P) program. LODs for
quantitative traits (ie, SOLAR and MERLIN-REGRESS) derive
from analysis of lipid levels from all family members of cohort 2.
For A through C, multipoint LODs for additional analyses can be
viewed in online Figure I and Tables II and VI and on our website. TC trait is cholesterol level ⱖage- and sex-specific 90th
percentile values; TG trait is triglyceride level ⱖ age- and sexspecific 90th percentile values (pink); and 95th FCHL lipid is
cholesterol or triglyceride level ⱖage- and sex-specific 95th percentile values (light blue). Genetic distances (from p terminus)
and marker information are available at the Marshfield Centre
for Human Genetics website.
We performed disease and quantitative linkage analyses to
evaluate the inheritance of lipid abnormalities in the most
common form of hyperlipidemia. The results identify 2 new
potential loci (chromosomes 6q16.1-q16.3 and 8p23.3-p22)
for FCHL and most importantly provide independent replication for a locus on chromosome 11p14.1-q12.1 that increases the transmission of the lipid abnormalities in this
highly atherogenic condition. The refined positional information provided by these studies should markedly accelerate the
identification of the FCHL-susceptibility gene associated
with this locus.
In our studies, we analyzed lipid and genotype data in all
FCHL family members, which enabled us to assess the
linkage data for chromosomes 6q16.1-q16.3, 8p23.3-p22,
10p11.22-10q21.1, and 11p14.1-q12.1 using different models. This multipronged approach, which was motivated by the
Naoumova et al
TABLE 4.
Locus
Confirmed and Candidate Loci for FCHL
2075
LODS on Chromosomes 6, 8 and 11 by Study
Analysis
Score LOD
GH-P
0.99
No. of Families
Disease
Trait*
Closest Marker
cM/Mbp
Reference
45
FCHL
CHL
D6S1056
102.0/94.1
This study
6
GH-P
0.95
6
SOLAR
3.0
0.018
45
FCHL
TG
D6S1056
102.0/94.1
This study
0.0001
44
TD2
TD2⬍25 y
D6S1056
102.0/94.1
6
GH-P
0.64
51
0.043
113
FCHL
95th FCHL lipid
D6S1671
107.9/100.6
This study
6
SOLAR
1.43
0.005
113
FCHL
Log (TG)
D6S1671
107.9/100.6
This study
6
6
GH-P
0.97
0.017
45
FCHL
95th FCHL lipid
D6S1021
112.2/104.7
This study
SOLAR
1.70
0.0026
232
Healthy
ApoCIII
D6S1021
112.2/104.7
6
31
MM/S
0.8
0.028
18
FCHL
CHL
D6S1021
112.2/104.7
9
8
GH-P
1.05
0.014
45
FCHL
95th FCHL lipid
D8S264
0.74/2.0
This study
8
MERLIN-REGRESS
1.69
0.003
113
FCHL
Log (TG)
D8S264
0.74/2.0
This study
8
MERLIN-REGRESS
2.20
0.0007
113
FCHL
Log (TC)
D8S277
8.34/6.8
This study
8
GH-P
0.96
0.0178
45
FCHL
CHL
D8S1106
26.0/12.7
This study
6
P Value
0.016
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8
GH-P
1.76
0.0022
113
FCHL
95th FCHL lipid
D8S549
31.7/15.6
This study
8
Allegro
2.11
0.0009
573
TD2
TD2
D8S549
31.7/15.6
39
11
MERLIN REGRESS
2.04
0.0011
113
FCHL
Log (TC)
D11S1324
35.2/29.7
This study
11
SOLAR
1.84
0.0018
232
Healthy
Total cholesterol
D11S1324
35.2/29.7
31
11
SOLAR
3.37
0.00004
32
TD2
Glucose
D11S1324
35.2/29.7
42
11
MM/S
3.08
0.00017
159
TD2
TD2
D11S935
45.9/36.7
52
11
GH-P
2.9
0.00014
113
FCHL
TG
D11S4083
47.1/37.2
This study
11
MERLIN REGRESS
2.7
0.0003
113
FCHL
Log (TG)
D11S4803
47.1/37.2
This study
11
SOLAR
3.72
0.00002
500
Prospective
LDL cholesterol
D11S1993
54.1/44.3
45
11
MM/S
2.6
0.00027
18
FCHL
FCHL
D11S1985
58.4/60.0
9
11
SOLAR
2.6
0.00027
113
FCHL
Log (TG)
D11S1985
58.4/60.0
This study
MM/S
2.71
0.00024
62
Obesity
LDL cholesterol
D11S1335
58.4/61.1
44
11
GH-P indicates GENEHUNTER-PLUS; MMS, MAPMAKER/SIBS; TD2, type 2 diabetes.
*Combined hyperlipidemia (CHL), triglyceride (TG), cholesterol, or triglyceride levels ⱖ 95th percentile age- and sex-specific values (95th FCHL lipid trait).
uncertainty of the inheritance of the lipid abnormalities in
FCHL,1,4 –10 has provided robust data for these loci, suggesting that it may be usefully applied in future studies to identify
additional susceptibility loci for this highly atherogenic
condition.
A QTL for serum triglyceride or apoCIII levels in the
chromosome 6q16.1-q16.3 genomic interval that acts as
FCHL susceptibility or modifier locus would be consistent
with the modest LODs obtained in the current and previous
studies.9,31 In a previous FCHL study, a maximized LOD of
0.8 at 111 cM was obtained for affection status in 18 extended
Dutch families.9 This compares with a triglyceride multipoint
LOD of 0.88 at 107.9 cM in white British FCHL families and
a multipoint LOD of 1.70 at 109 cM for the triglyceriderelated trait, apoCIII, in 232 multigenerational pedigrees,
ascertained without regard for health through households
with ⱖ2 schoolchildren.31
The estimated position of a QTL or disease trait locus
commonly varies in complex genetic disorders,38 which may
be attributable to chance variation around a single locus, the
presence of multiple genes, incomplete penetrance, variation
in the expression of the phenotype, ascertainment bias, and
genetic heterogeneity. In the present study, we used 2 cohorts
of families, both of which are likely to be genetically
heterogeneous. In addition, we used dichotomised and quantitative trait linkage analyses, which necessarily extracts
different genetic information from the families to compute
estimates of gene location. Our data for the candidate locus
on chromosome 8 produced the most discrepant estimates for
gene location and varied according to both the type of
analysis performed and the cohort examined. However, reasonable concordance was observed between 2 analyses. The
dichotomised trait linkage analysis performed on all 158
FCHL individuals (ie, cohorts 1 and 2) produced a LOD of
1.80 at 11.1 cM for the 95th percentile FCHL lipid trait and
was supported by a QTL (LOD, 2.2) for cholesterol levels at
8.4 cM in our second cohort of families (Figure, panel B). In
the UK population, the interval, close to marker D8S549 at
31.7 cM, has also been implicated in type 2 diabetes39 (Table
4). Type 2 diabetes was a specific exclusion criterion in the
present study. However, because previous studies have indicated that patients with FCHL may have impaired glucose
tolerance and insulin resistance,8,19,21,24,40,41 some of the
linkage signals we obtained close to this marker in our
analyses might relate to a common metabolic abnormality in
FCHL and type 2 diabetes.
The data from the present and previous studies (Table 4)
provide compelling evidence that the chromosome 11p14.1-
2076
Arterioscler Thromb Vasc Biol.
November 2003
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q12.1 genomic interval contains a QTL for serum cholesterol
and triglyceride, which may act as an FCHL susceptibility or
modifier locus. In FCHL, Aouizerat et al9 obtained a maximized nonparametric LOD of 2.6 at 65 cM for affection status
(defined by either high cholesterol or triglyceride levels) in
18 extended Dutch FCHL families, which was supported by
genotype data in an additional 17 Dutch FCHL families.
However, these additional data shifted the estimated position
of the causative gene closer to marker D11S1324 at 35.2 cM.
In the present study, we used a denser set of markers to
evaluate the 11p14.1-q12.1 interval and obtained the highest
LODs (2.7 to 3.05) for the triglyceride component of this
condition between 48.7 and 58.4 cM. This interval also
resides in close proximity to a QTL for impaired glucose
intolerance,42 suggesting that a common metabolic abnormality, such as insulin resistance, in FCHL and type 2 diabetes
might contribute to the development of the triglyceride
abnormalities in these conditions. The results for this interval
are unlikely to be attributable to sequence variants at the
APOAI/CIII/AIV/AV locus,43 because this gene cluster is
located within the 11q23.1 locus at 121 cM, some 73 cM
from the peak of the linkage signal for serum triglyceride
levels.
We also obtained evidence for a QTL for serum cholesterol
at 35.2 cM, which raises the issue of whether the 11p14.1q12.1 genomic interval might contain separate susceptibility
alleles for the different lipid abnormalities (ie, cholesterol and
triglyceride) of FCHL. In support of this, Klos et al31 found
evidence for a cholesterol QTL (LOD, 1.84) at 35 cM in 232
multigenerational pedigrees, ascertained without regard for
health through households with ⱖ2 schoolchildren,31 but no
such evidence for a serum triglyceride QTL. Instead, the
highest LOD (0.13) for this trait was produced at 113 cM,
close to the APOAI/CIII/AIV/AV gene cluster. Similarly, 2
additional studies produced evidence for a LDL cholesterol
QTL within the 11p14.1-q12.1 genomic interval (Table 4) but
no such evidence for a triglyceride QTL.44,45 The first study
involved 62 nuclear families, ascertained through 2 obese
siblings, whereas the second studied 2799 subjects from the
NHLBI Family Heart Study.
The failure to detect linkage of the 11p14.1-q12.1 locus to
FCHL in our first cohort of 45 FCHL families does not
detract from our replication data. Subtle differences in family
structures or the frequency of a disease-causing allele within
families can have a substantial impact on the power to detect
linkage in genome-wide screen studies, and this is especially
true for small data sets.46 – 48 Indeed, our inability to replicate
the evidence for linkage of 11p14.1-q12.1 to FCHL in our
first data set has parallels with many genome-wide screens.
The Crohn’s chromosome 16 locus, for example,49 produced
a NPL score of 3.17 in the original data set, compared with
scores of ⬍0.7 in subsequent studies.
A final NPL value of 3.47 in Crohn’s disease proved
sufficient for identifying 3 susceptibility alleles for this
condition,50 suggesting that the NPL⫹ value of 3.63 obtained
for the 11p14.1-q12.1 chromosomal region in the present
study will lead to the identification of sequence variants that
impact serum triglyceride levels in FCHL as well as cholesterol levels. This would increase the likelihood of cloning
additional genes in this condition through ordered subset
analysis and identifying the primary metabolic pathway that
is perturbed in FCHL and the associated metabolic syndrome
of insulin resistance, which will presumably influence the
development of new therapies to treat the substantially
increased risk of CHD that is associated with these
conditions.
Appendix
Electronic Database Information
Family details and data: http://www.csc.mrc.ac.uk/ResearchGroups/
GenomicAndMolecularMedicine/Home/home.html; Centre for Medical Genetics, Marshfield Medical Research Foundation: http://
research.marshfieldclinic.org/genetics/; Project Ensembl: http://
www.ensembl.org/; Genome database: http://www.gdb.org/;
MERLIN: http://www.sph.umich.edu/csg/abecasis/merlin; SOLAR:
http://www.sfbr.org/sfbr/public/software/solar/index.html; National
Public Health Institute of Finland, Department of Human Molecular
Genetics: http://www.ktl.fi/molbio/wwwpub/fchl/genomescan
Acknowledgments
The authors gratefully acknowledge support from the British Heart
Foundation (PG/98159, PG2001015), Medical Research Council,
Hammersmith Hospitals NHS Trust, London, UK, and the Marshfield Medical Research Foundation. They are also indebted to all
study participants and coinvestigators, including Saro Niththyananthan, Georgina Harrison, Rebecca Francombe, Louise Olofsson,
Susan Earl-Mitchell, and John Batty. They also thank Professor
Timothy Aitman, Drs Arjen Mensenkamp and Penelope Ritchie for
helpful discussion, Dr David Perkins for programming assistance,
Professor Pak Sham and Dr David Curtis for guidance on the
quantitative and parametric analyses, and Rocio Lale-Montes for
excellent secretarial assistance.
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Confirmed Locus on Chromosome 11p and Candidate Loci on 6q and 8p for the
Triglyceride and Cholesterol Traits of Combined Hyperlipidemia
Rossitza P. Naoumova, Stephanie A. Bonney, Sophie Eichenbaum-Voline, Hetal N. Patel,
Bethan Jones, Emma L. Jones, Joanna Amey, Susan Colilla, Clare K.Y. Neuwirth, Rebecca
Allotey, Mary Seed, D. John Betteridge, David J. Galton, Nancy J. Cox, Graeme I. Bell, James
Scott and Carol C. Shoulders
Arterioscler Thromb Vasc Biol. 2003;23:2070-2077; originally published online September 18,
2003;
doi: 10.1161/01.ATV.0000095975.35247.9F
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
Greenville Avenue, Dallas, TX 75231
Copyright © 2003 American Heart Association, Inc. All rights reserved.
Print ISSN: 1079-5642. Online ISSN: 1524-4636
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://atvb.ahajournals.org/content/23/11/2070
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Fig. S1
1
0.5
0
1.5
1
0
50
100
150
200
250
300
1.5
2
1
0.5
0.5
0
0
0
2
50
100
150
200
250
300
4
1
1
0.5
0.5
0
5
0
100
150
50
100
150
200
150
50
100
150
1
0.5
150
50
100
13
100
1
75
100
25
50
75
100
1.5
0
50
100
150
200
125
15
0
0
125
16
0.5
25
50
0.5
0
0
0
1
14
0.5
0
75
12
0.5
150
1
1
50
150
200
0.5
25
100
0
0
0
50
1
11
0
0
100
200
9
0
200
0.5
10
50
150
200
1
0
100
0
0
100
50
0.5
0
0
250
0
1
0.5
0.5
50
200
1.5
8
1
7
0
150
6
0
1.5
1
100
1
200
1.5
50
0.5
0
50
0
1.5
1.5
0
3
1
125
0
25
50
75
100
1
17
1
0.5
0.5
0
125
18
0
25
50
75
100
125
0
0
1
25
50
75
100
125
150
1
19
0.5
21
0.5
2
0
0
25
50
75
100
20
0
0
1.5
1
1
22
0.5
0.5
0
0
0
25
50
0
25
50
75
100
25
50
TG (1)
CHL (2)
TC (3)
th
95 FCHL lipid trait (4)
75
Table S1. Loci examined in second cohort of families, and marker positions.
Locus
Genomic Interval Markers
cM
1
1q23.3
D1S104, D1S1677
175.6-175.6
2
2p25.1
D2S2952, D2S2164
17.9-18.4
3
2q32.1-q33.3
4
3q24
5
4q21.3-q23
6
4q35.1
7
7q34-q36.2
8
9p21.1
9
9q21.13-q21.32
10
12q24.33
11
13q22.3-q31.1
D13S1318, D13S800, D13S162
53.2-58.5
12
17p11.2-q11.2
D17S2196, D17S1294
44.6-50.7
13
20p12.2-p12.1
D20S162, D20S186, D20S604, D20S470
24.7-39.3
14
20q12.1-q13.12
D20S107, D20S119, D20S481, D20S836
55.7-64.9
15
21q21.1-q21.2
D21S1437, D21S1435
13.1-18.1
16
3p21.31-p14.2
D3S2384, D3S1766, D3S1600
70.6-86.0
17
4p16.2-p16.1
D4S432, D4S2366, D4S2983
6.8-17.5
18
5q34-q35.1
D5S415, D5S1456, D5S2069
169.5-182.4
19
7p12.1
D7S1830
72.8
20
8q24.21
D8S1128
139.5
21
10q26.3
D10S1248, D10S212, D10S169
22
14q11.2-q12
23
15q26.2-q26.3
D2S1776, D2S1391, D2S1384
D3S1744
D4S2361, D4S1647, D4S2986
D4S408
D7S2560, D7S1824, D7S661, D7S2195, D7S3070
D9S1118
D9S301, D9S175, D9S1122, D9S922
D12S1659
D14S1023, D14S50
D15S816, D15S207, D15S657, D15S87
173.0-200.4
161.0
93.5-105.3
195.0
145.3-163.0
58.3
66.3-80.1
155.9
165.3-173.1
8.3-12.5
100.6-115.9
24
20p11.22
25
2q35-q36.3
D20S477
D2S434, D2S1242, D2S126, IRS-1, D2S228,
47.5
216-229.1
D2S2158
26
6q15-q16.3
D6S1613, D6S1056, D6S1671, D6S1021
27
8p23.3-p22
D8S264, D8S277, D8S1825, D8S1721, D8S1130,
97.1-112.2
0.7-40.7
D8S1106, D8S549, D8S1731and LPLCA-B
28
10p11.22-q21.1
D10S183, D10S1208, D10S1220, D10S1756
60.6-75.6
29
11p15.2-q12.1
D11S1981, D11S915, D11S1324, D11S1392,
21.5-61.8
D11S4083, D11S905, D11S1985, D11S4191,
D11S1765
Table S2. Multipoint LODs for Combined Datasets by Marker*
cM
Cholesterol
Triglyceride
95th FCHL Lipid
CHL
D6S1613
97.1
0.0322
0.7765
0.3105
0.9307
D6S1056
102.8
0.0185
0.6803
0.4599
0.8885
D6S1671
107.9
0.0269
0.8770
0.7870
0.6114
D6S1021
112.2
0.0000
0.4620
0.3186
0.2644
D8S264
0.7
0.5040
0.0000
0.8815
0.0000
D8S277
8.3
0.7045
0.6673
1.7304
0.5749
D8S1825
15.4
0.6441
0.9835
1.6589
0.8706
D8S1721
17.0
0.4639
0.7888
1.3531
0.6060
D8S1130
22.4
0.0647
0.3603
0.7254
0.2862
D8S1106
26.4
0.6883
0.8741
1.3838
1.1059
D8S511
30.5
0.7581
0.9210
1.4392
0.9413
D8S549
31.7
0.5832
0.7876
1.2319
0.6925
Lplca-b
41.5
0.2558
0.2376
0.5356
0.1770
D10S183
60.6
0.0000
0.1729
0.0413
0.1155
D10S1208
63.3
0.0000
0.4005
0.1034
0.3279
D10S1220
70.2
0.0000
0.5500
0.4478
0.5992
D10S1756
75.6
0.0000
0.1275
0.2827
0.2482
D11S1981
21.5
0.0124
0.3625
0.0000
0.3664
D11S915
30.9
0.2048
1.1570
0.1223
0.7629
D11S1324
35.2
0.2911
1.1908
0.2335
0.5216
D11S1392
43.2
0.1269
1.3030
0.0619
0.7395
Markers
D11S4083
47.1
0.1039
2.0806
0.2130
1.5010
D11S905
52.0
0.2464
2.1652
0.4016
1.5901
D11S1985
58.4
0.0629
1.0241
0.0271
0.6876
D11S4191
60.1
0.1125
0.8313
0.0428
0.5175
D11S1765
61.8
0.0886
0.7600
0.0683
0.4778
*LODS between intervals have been deposited on our website.
Table S3. Parametric Two Point Linkage Results for Chromosomes 6, 8, 10 & 11*.
Marker
LOD†/NPL‡
Distance
CHL§
TG║
TC¶
95th FCHL Lipid#
D6S1613
97.1
0.1708 / 1.03015
0.7729 / 1.04038
0.0974 / -0.00414
0.0000 / 0.22753
D6S1056
102.8
0.0111 / -0.01717
0.3126 /-0.12574
0.0000 / -0.31638
0.0000 / -0.45025
D6S1671
107.9
0.1112 / 0.79522
1.9127/ 1.51557
0.1323 / 0.47766
0.1368 / 1.21115
D6S1021
112.2
0.0401 / -0.11131
0.2918 / 0.44980
0.0063 / -0.51927
0.0000 / -0.33174
D8S264
0.7
0.0000 / -0.59254
0.0000 / -0.90197
0.3078 / -0.05361
0.0251 / 0.31470
D8S277
8.3
0.1384 / 0.75796
0.3119 / 1.11609
0.0000 / 0.35443
0.5018 / 1.55182
D8S1825
15.4
0.2332 / 1.06022
0.5304 / 0.89170
0.0487 / 0.47206
0.7988 / 1.33655
D8S1721
17.0
0.0000 / 0.31485
0.1193 / 0.73189
0.0000 / -0.62548
1.2698 / 1.25553
D8S1130
22.4
0.0172 / 0.20760
0.0231 / 0.39406
0.0000 / -0.37843
0.1445 / 0.89471
D8S1106
26.4
0.5905 / 0.63427
1.1682 / 0.92481
0.0000 / -0.38586
0.3954 / 1.02276
D8S511
30.5
0.0001 / 0.65736
0.5165 / 0.70610
0.1753 / 0.47293
0.7255 / 1.20293
D8S549
31.7
0.0000 / 0.16427
0.4618 / 0.58567
0.3843 / 0.84870
1.6935 / 1.19257
Lplca-b
41.5
0.0000 / -0.61105
0.6027 / 1.28232
0.0000 / -0.23176
0.1226 / 0.10974
D8S1128
139.5
0.0066 / -0.17668
0.0000 / -0.46131
0.0004 / -0.01226
0.4220 / 0.42768
D10S183
60.6
0.2613 / 0.64303
0.0537 / 0.63386
0.1124 / -0.02811
0.3209 / 0.37042
D10S1208
63.3
0.1949 / 0.40242
0.0000 / 0.55845
0.1774 / -0.11427
0.0000 / -0.13479
D10S1220
70.2
0.5636 / 0.42757
0.4457 / 0.77823
0.0749 / 0.45904
0.9295 / 1.15608
D10S1756
75.6
0.4069 / 0.90105
0.0747 / 0.57919
0.5169 / 0.61188
0.6416 / 0.84280
D10S1248
165.3
0.1172 / 0.44886
0.0004 / 0.16838
0.0007 / 0.27752
0.0000 / 0.02653
D10S212
170.9
0.0000 / -0.01954
0.0000 / -0.06050
0.1788 / 0.74681
0.0116 / 0.76324
D10S169
173.1
0.1360 / 0.75644
0.0301 / 0.55143
0.1543 / 0.84557
0.0799 / 0.75421
D11S1981
21.5
0.3421 / 0.43381
0.5209 / 0.56388
0.0459 / -0.14607
0.0075 / -0.07821
D11S915
30.9
0.8682 / 1.16943
1.6678 / 1.78551
0.0760 / 1.04415
0.2943 / 1.20439
D11S1324
35.2
0.1305 / 0.72001
0.2945 / 1.15495
0.0073 / 0.91352
0.0000 / 0.84539
D11S1392
43.2
0.2833 / 0.78157
0.1390 / 0.81622
0.0096 / 0.61998
0.0909 / 0.73294
D11S4083
47.1
2.5506 / 1.89653
3.0548 / 2.17416
0.6075 / 0.98096
1.0008 / 1.39558
D11S905
52.0
0.2668 / 1.22680
0.5985 / 1.61183
0.0563 / 0.71885
0.1808 / 0.99549
D11S1985
58.4
0.6538 / 1.44102
0.6816 / 1.61409
0.0292 / 0.78825
0.4869 / 1.11906
D11S4191
60.1
0.0381 / 0.55925
0.1344 / 0.85697
0.0143 / 0.76198
0.0184 / 0.51121
D11S1765
61.8
0.7860 / 1.09261
0.7893 / 1.04224
0.2626 / 0.98548
0.2999 / 0.81445
*Cohort 1, two point LODs/NPL for chromosomes 6, 8,10 and 11 have been deposited on our website
†
Dominant model using all family members
‡
Non parametric linkage values for affected sib and relative pairs
§
CHL = Combined Hyperlipidemia, cholesterol and triglyceride levels > age-specific 90th percentile values.
║
TG = Triglyceride level > age-specific 90th percentile values.
¶
TC = Cholesterol level > age-specific 90th percentile values.
#
95th FCHL Lipid = Cholesterol or triglyceride level > age-sex-specific 95th percentile values.
Table S4. Two Point SOLAR LOD Scores on Chromosomes 6, 8, 10 & 11 for log (Triglyceride), log (Cholesterol) and ApoB* by Marker
Log (Triglyceride)
Marker
cM
LOD
D6S1613
97.1
0.8657
D6S1056
102.8
D6S1671
H2q1‡
ApoB†
Log (Cholesterol)
LOD
H2q1
LOD
H2q1
0.139488
0.1050
0.048296
0.0017
0.009164
0.2380
0.073956
0.0972
0.048170
0.0000
0.000000
107.9
1.7653
0.195538
0.2000
0.062673
0.0000
0.000000
D6S1021
112.2
0.0048
0.013389
0.0092
0.014441
0.0000
0.000000
D8S264
0.7
0.0000
0.000000
0.0653
0.037894
0.0637
0.054815
D8S277
8.3
0.1667
0.071449
0.0000
0.000000
0.2926
0.121512
D8S1825
15.4
0.2643
0.082940
0.0166
0.019643
0.0000
0.000000
D8S1721
17.0
0.4889
0.118026
0.0000
0.000000
0.2836
0.125084
D8S1130
22.4
0.0335
0.028184
0.0000
0.000000
0.0000
0.000000
D8S1106
26.4
0.0341
0.030832
0.0010
0.005191
0.0000
0.000000
D8S511
30.5
0.2785
0.091677
0.0000
0.000000
0.0109
0.027573
D8S549
31.7
0.3019
0.083801
0.0000
0.000000
0.3340
0.127221
Lplca-b
41.5
0.0008
0.008024
0.0004
0.006463
0.0000
0.000000
D10S183
60.6
0.7091
0.134866
0.1718
0.060018
0.0030
0.012851
D10S1208
63.3
0.0000
0.000000
0.0000
0.000000
0.0000
0.000000
D10S1220
70.2
0.0245
0.031246
0.0284
0.028403
0.0000
0.000000
D10S1756
75.6
1.4035
0.180695
0.0378
0.028451
0.1395
0.082468
D11S1981
21.5
1.2353
0.184787
0.0629
0.033488
0.0000
0.000000
D11S915
30.9
0.1635
0.062009
0.1193
0.051005
0.0709
0.057906
D11S1324
35.2
0.0002
0.002644
0.0000
0.000000
0.0000
0.000000
D11S1392
43.2
0.6634
0.130432
0.0000
0.000000
0.0000
0.000000
D11S4083
47.1
2.6947
0.241061
0.1364
0.057314
0.0071
0.020214
D11S905
52.0
1.5009
0.187340
0.1737
0.067173
0.0000
0.000000
D11S1985
58.4
3.3554
0.287435
0.0979
0.048083
0.0000
0.000000
D11S4191
60.1
1.0623
0.161004
0.0000
0.000000
0.0000
0.000000
D11S1765
61.8
0.7394
0.139502
0.0007
0.004026
0.0000
0.000000
*LODs for HDL- and LDL-Cholesterol, and log (triglyceride)/HDL-Cholesterol ratio have been deposited on our website.
†
Heritability estimates for log (triglyceride), log (cholesterol) and apoB = 38.61±6.5%, 48.26±6.7% and 39.65±8.0% respectively. All P values <1x10-7.
‡
Estimate of variance in lipid levels attributable to an allele(s) at each marker locus.
Table S5. Two Point “MERLIN-REGRESS” LODs on Chromosomes 6q, 8p, 10p, 11p by Marker.
Log (Triglyceride)*
LOD
H2
Log (Cholesterol)
LOD
H2
ApoB
Marker
cM
LOD
H2
D6S1613
97.1
0.642
0.079 ± 0.046
-0.013
-0.001 ±0.003
0.109
0.059 ± 0.084
D6S1056
102.8
0.883
0.102 ± 0.051
0.115
0.003 ± 0.004
0.322
0.116 ± 0.095
D6S1671
107.9
0.460
0.067 ± 0.046
0.005
0.001 ± 0.004
-0.001
-0.007 ± 0.086
D6S1021
112.2
0.042
0.023 ± 0.052
-0.191
-0.004 ± 0.004
-0.101
-0.065 ± 0.096
D8S264
0.7
0.416
0.069 ± 0.050
0.490
0.006 ± 0.004
0.063
0.047 ± 0.087
D8S277
8.3
0.191
0.048 ± 0.051
1.224
0.010 ± 0.004
0.521
0.144 ± 0.093
D8S1825
15.4
0.111
0.042 ± 0.058
1.204
0.015 ± 0.006
0.081
0.065 ± 0.107
D8S1721
17.0
0.307
0.068 ± 0.058
0.318
0.006 ± 0.005
0.503
0.159 ± 0.105
D8S1130
22.4
0.287
0.062 ± 0.054
0.015
0.001 ± 0.004
0.403
0.135 ± 0.099
D8S1106
26.4
0.467
0.089 ± 0.061
0.666
0.009 ± 0.005
0.134
0.090 ± 0.115
D8S511
30.5
0.043
0.026 ± 0.059
0.057
0.003 ± 0.006
0.150
0.114 ± 0.137
D8S549
31.7
0.288
0.104 ± 0.090
3.052
0.038 ± 0.010
0.254
0.219 ± 0.203
Lplca-b
41.5
0.165
0.067 ± 0.077
-0.038
-0.002 ± 0.006
-0.042
-0.058 ± 0.131
D10S183
60.6
0.535
0.092 ± 0.059
0.036
0.002 ± 0.004
0.149
0.077 ± 0.093
D10S1208
63.3
-0.059
-0.032 ± 0.062
0.008
0.001 ± 0.005
-0.019
-0.031 ± 0.105
D10S1220
70.2
0.184
0.061 ± 0.066
0.115
0.005 ± 0.006
0.496
0.183 ± 0.121
D10S1756
75.6
0.803
0.100 ± 0.052
-0.058
-0.002 ± 0.004
0.849
0.217 ± 0.110
D11S1981
21.5
0.180
0.047 ± 0.051
-0.394
-0.005 ± 0.004
-0.485
-0.136 ± 0.091
D11S915
30.9
-0.015
-0.013 ± 0.049
1.774
0.013 ± 0.005
0.015
0.024 ± 0.090
D11S1324
35.2
0.240
0.051 ± 0.048
1.517
0.011 ± 0.004
0.102
0.060 ± 0.087
D11S1392
43.2
0.761
0.103 ± 0.055
-0.021
-0.002 ± 0.005
-0.231
-0.109 ± 0.106
D11S4083
47.1
1.924
0.140 ± 0.047
0.055
0.002 ± 0.004
0.018
0.026 ± 0.090
D11S905
52.0
1.501
0.135 ± 0.051
0.251
0.005 ± 0.004
-0.194
-0.092 ± 0.098
D11S1985
58.4
1.728
0.138 ± 0.049
0.360
0.005 ± 0.004
-0.035
-0.036 ± 0.091
D11S4191
60.1
0.574
0.078 ± 0.048
0.020
0.001 ± 0.004
-0.106
-0.063 ± 0.089
D11S1765
61.8
0.691
0.094 ± 0.053
0.359
0.006 ± 0.005
-0.028
-0.035 ± 0.096
* LODs for HDL- and LDL-Cholesterol, and log (Triglyceride)/HDL-Cholesterol ratio have been deposited on our website.
Table S6. Multipoint “MERLIN-REGRESS” LODs on Chromosomes 6, 8, 10, 11
Log (Triglyceride)*
LOD
H2
Log (Cholesterol)
LOD
H2
ApoB
Marker
cM
LOD
H2
D6S1613
97.1
0.705
0.079 ± 0.044
-0.055
-0.002 ± 0.003
0.106
0.055 ± 0.078
D6S1056
102.8
0.596
0.073 ± 0.044
0.001
0.000 ± 0.003
0.097
0.052 ± 0.078
D6S1671
107.9
0.538
0.068 ± 0.043
0.003
0.000 ± 0.003
0.001
0.004 ± 0.078
D6S1021
112.2
0.116
0.033 ± 0.045
-0.037
-0.001 ± 0.003
0.005
0.012 ± 0.083
D8S264
0.7
1.389
0.121 ± 0.048
0.797
0.007 ± 0.003
0.041
0.035 ± 0.081
D8S277
8.3
1.109
0.108 ± 0.048
2.200
0.011 ± 0.003
0.541
0.132 ± 0.084
D8S1825
15.4
0.994
0.097 ± 0.046
1.293
0.008 ± 0.003
0.464
0.121 ± 0.083
D8S1721
17.0
1.254
0.110 ± 0.046
0.925
0.007 ± 0.003
0.735
0.151 ± 0.082
D8S1130
22.4
0.460
0.066 ± 0.045
0.279
0.004 ± 0.003
0.548
0.132 ± 0.083
D8S1106
26.4
0.328
0.058 ±0.047
0.852
0.007 ± 0.003
0.475
0.130 ± 0.088
D8S511
30.5
0.602
0.080 ± 0.048
0.732
0.007 ± 0.004
1.083
0.206 ± 0.092
D8S549
31.7
0.610
0.082 ± 0.049
0.682
0.007 ± 0.004
1.112
0.212 ± 0.094
Lplca-b
41.5
0.086
0.035 ± 0.056
0.270
0.005 ± 0.004
0.249
0.120 ± 0.112
D10S183
60.6
0.268
0.052 ± 0.047
-0.048
-0.002 ± 0.003
0.069
0.046 ± 0.080
D10S1208
63.3
0.288
0.055 ± 0.048
-0.063
-0.002 ± 0.003
0.339
0.102 ± 0.082
D10S1220
70.2
0.245
0.052 ± 0.049
0.003
0.000 ± 0.004
0.311
0.102 ± 0.085
D10S1756
75.6
0.673
0.084 ± 0.048
-0.003
-0.000 ± 0.003
0.882
0.178 ± 0.088
D11S1981
21.5
0.206
0.045 ± 0.046
-0.039
-0.001 ± 0.003
-0.443
-0.119 ± 0.083
D11S915
30.9
0.085
0.028 ± 0.044
1.568
0.009 ± 0.003
0.000
0.001 ± 0.079
D11S1324
35.2
0.658
0.076 ± 0.044
2.042
0.010 ± 0.003
-0.003
-0.009 ± 0.079
D11S1392
43.2
1.576
0.122 ± 0.045
0.927
0.007 ± 0.003
-0.014
-0.020 ± 0.080
D11S4083
47.1
2.543
0.148 ± 0.043
1.043
0.007 ± 0.003
0.004
0.011 ± 0.079
D11S905
52.0
2.056
0.134 ± 0.044
0.968
0.007 ± 0.003
-0.003
-0.009 ± 0.082
D11S1985
58.4
1.985
0.132 ± 0.044
1.258
0.007 ± 0.003
-0.149
-0.064 ± 0.078
D11S4191
60.1
2.018
0.137 ± 0.045
1.000
0.007 ± 0.003
-0.148
-0.064 ± 0.078
D11S1765
61.8
0.903
0.092 ± 0.045
0.588
0.005 ± 0.003
-0.190
-0.074 ± 0.080
* LODs for HDL- and LDL-Cholesterol, and log (Triglyceride)/HDL-Cholesterol ratio have been deposited on our website.