Genome‐Wide Family‐Based Linkage Analysis of Exome Chip Variants and Cardiometabolic Risk

Abstract

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.

A genome‐wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study

“…The two variants are poorly correlated ( r 2 = 0.05) and analysis conditioned on rs36229491 failed to abolish the rs35874588 signal, suggesting at least two independent signals exist. These results were consistent with previous findings and rs36229491 and rs35874588 were in strong LD with previously identified SNPs rs3764261 and rs5882 ( r 2 = 0.98 and 0.95, respectively; Hellwege, Palmer, Raffield, ; Willer et al., ).…”

Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels

“…These included individually genotyped SNPs at the ADIPOQ locus (n=33)(An et al 2012; An et al 2013) which were combined with data from 7497 SNPs in the ADIPOQ region (chr3:161,560,463-197,838,262, hg19, 25 MB proximal and to the distal end of the chromosome) derived from Illumina OmniExpress (GWAS chip) genome-wide genotyping as part of the GUARDIAN Consortium(Goodarzi et al 2013) and data from all chromosome 3 SNPs (n=3428) on the Illumina HumanExome Beadchip(Hellwege et al 2014) for a total of 10,958 non-redundant, polymorphic SNPs. Quality control for each group of SNP data has previously been described in detail(An et al 2012; Hellwege et al 2014). All datasets underwent Mendelian error checking using PedCheck(O'Connell and Weeks 1998).…”

Genome‐wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans

“…Thus, associations of SNPs at the CMIP locus with T2D and biomarkers related to insulin resistance in individuals of EUR and EAS descent may reflect an underlying interaction with rs10830963 that is partially unmasked in these populations. In IRASFS, neither previously reported SNPs in the CMIP region nor the interacting SNP rs17197883 showed evidence of association with measures of insulin sensitivity, adiponectin levels, WHR adjusted for BMI, nor fasting glucose (Gao et al., ; Hellwege et al., ). However, two previously reported SNPs at the CMIP locus, rs2925979 ( P = 0.02) and rs56823429 ( P = 0.009), and the interacting SNP rs17197883 ( P = 0.002) were nominally associated with HDL cholesterol in IRASFS Hispanics (Hellwege et al., ).…”