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

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