Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Québec Family Study

Y Bossé,Y.C Chagnon,J-P Després,T Rice,D.C Rao,C Bouchard,L Pérusse,M-C Vohl

doi:10.1194/jlr.m300401-jlr200

Abstract

A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Québec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method. In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage.

Highlights

A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels
Before the genome-scan analysis, total cholesterol, triglyceride, LDL-C, and HDL-C levels were adjusted in a stepwise manner for the effects of age, age2, age3, gender, and Body mass index (BMI)
These covariates accounted for 0–15.3%, 5.7–30.2%, 0–10.6%, and 6.6–32.2% of the total phenotypic variation in total cholesterol, triglyceride, LDL-C, and HDL-C, respectively, depending on the age-by-sex groups

Summary

Introduction

A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method This genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Genes accountable for several monogenic dyslipidemias have been identified [3], those underlying the variation in the population at large remain to be found These results have motivated several investigators to use the genomescan approach to identify chromosomal regions harboring genes controlling lipoprotein/lipid levels. Such an approach has the ability to find quantitative trait loci (QTLs) without being dependent on an understanding of the physiology governing the traits. Genome-wide evidence of linkage has been reported on 2q in Hutterites [17], 10p in Finnish families [18], 15q in a second set of Mexican Americans ascertained for type 2 diabetes [19], and 19q in white Utah families [20]

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