Linkage and association analyses identify a candidate region for apoB level on chromosome 4q32.3 in FCHL families

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Abstract
Familial combined hyperlipidemia (FCHL) is a complex trait leading to cardiovascular disease (CVD) risk. Elevated levels and size of apolipoprotein B (apoB) and low-density lipoprotein (LDL) are associated with FCHL, which is genetically heterogeneous and is likely caused by rare variants. We carried out a linkage-based genome scan of four large FCHL pedigrees for apoB level that is independent of LDL: apoB level that is adjusted for LDL level and size. Follow-up included SNP genotyping in the region with the strongest evidence of linkage. Several regions with the evidence of linkage in individual pedigrees support the rare variant model. Evidence of linkage was strongest on chromosome 4q, with multipoint analysis in one pedigree giving LOD = 3.1 with a parametric model, and a log Bayes Factor = 1.5 from a Bayesian oligogenic approach. Of the 293 SNPs spanning the implicated region on 4q, rs6829588 completely explained the evidence of linkage. This SNP accounted for 39% of the apoB phenotypic variance, with heterozygotes for this SNP having a trait value that was ~30% higher than that of the high-frequency homozygote, thus identifying and considerably refining a strong candidate region. These results illustrate the advantage of using large pedigrees in the search for rare variants: reduced genetic heterogeneity within single pedigrees coupled with the large number of individuals segregating otherwise-rare single variants leads to high power to implicate such variants.