Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1,205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 LOD scores with 1,148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (pT in APOA5, and triglyceride levels (p=3.67×10-10). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to dbSNP build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.
Tabb, K. L., Hellwege, J. N., Palmer, N. D., Dimitrov, L., Sajuthi, S., Taylor, K. D., Ng, M. C., Hawkins, G. A., Chen, Y. I., Brown, W. M., McWilliams, D., Williams, A., Lorenzo, C., Norris, J. M., Long, J., Rotter, J. I., Curran, J. E., Blangero, J., Wagenknecht, L. E., Langefeld, C. D., … Bowden, D. W. (2017). Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study. Annals of human genetics, 81(2), 49–58. https://doi.org/10.1111/ahg.12184
Annals of human genetics
Office of Human Genetics