Genome-wide family-based linkage analysis of exome chip variants and cardiometabolic risk

Linkage analysis of complex traits has had limited success in identifying trait-influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African-American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two-point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P-value = 4 × 10^-19) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P-value <4.6 × 10^-12), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.