Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans

Abstract

Linkage studies of complex genetic diseases have been largely replaced by Genome-Wide Association studies (GWAS), due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates reexamination of family-based methods. In this study we investigated the performance of two-point linkage analysis for over 1.6 million SNPs combined with single variant association analysis to identify high impact variants which are both strongly linked and associated with cardiometabolic traits in up to 1 414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD scores with 9 214 LOD scores ≥ 3.0, 845 ≥ 4.0, and 89 ≥ 5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for TNFα receptor 2). Twenty-seven variants were associated with p < 0.005 as well as having a LOD score > 4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31Mb) on chromosome 1q with acute insulin response (max LOD = 5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.

Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study

“…Additional broad linkage peaks included a region on chromosome 1 with acute insulin response (33 variants with LOD >3 in the peak and 3 with LOD >4; Table S4) and a region on chromosome 12 with adiponectin levels (adjusted for G45R), both consistent with our previous findings (Hellwege et al., ). A smaller region on chromosome 6 was observed to show evidence of linkage with WHR_BMI.…”

“…While we did observe linkage peaks on chromosomes 1 (acute insulin response) and 12 (G45R‐adjusted adiponectin levels) consistent with our previous report (Hellwege et al., ), the signals in the current report were not found to be as strong. This is likely due to the difference in sample sizes between the two studies; the exome chip analysis included up to 1414 participants from 90 families compared with 1205 samples from 78 families in the exome sequencing analysis.…”

“…The measured genotype analysis, which accounts for the nonindependence of family members, involves incorporating each variant separately in a model as a measured covariate (the number of copies of the minor allele) evaluating genotype‐specific differences in the trait means. These approaches have been documented in detail previously (Hellwege et al., , ). Waist‐to‐hip ratio (WHR), waist circumference, visceral adipose tissue area (VAT), and visceral to subcutaneous tissue ratio (VSR) were evaluated both with and without adjustment for BMI.…”

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., ).…”

“…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., ). The interacting CMIP variant, rs17197883, was not associated with T2D in the current study in a model adjusted for age, sex, and PC1 ( P = 0.19).…”