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

Abstract

Summary 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 (p<5×10-08), with the strongest association between rs651821:C>T 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.

Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS)

“…All sequence reads passed through the Illumina Data Analysis Pipeline, and those from samples passing QC criteria were mapped to the human genome reference sequence (hg19). A detailed description of the sequencing platform and analysis pipeline has been published 36 . Of note, multi-sample recalibration was performed prior to variant calling.…”

Established and emerging strategies to crack the genetic code of obesity

“…A similar study in the same population identified a low‐frequency variant (rs2076349) in the laminin subunit beta 3 ( LAMB3 ) gene associated with morbid obesity and BMI . A whole‐exome single‐variant association analysis in 1,205 Hispanic Americans (78 families) identified a low‐frequency variant (rs11554137) in the isocitrate dehydrogenase 1 ( IDH1 ) gene associated with BMI at the conventional genome‐wide level of significance . WES in 177 Pima Indians followed by targeted genotyping in >13,000 additional subjects identified two common SNPs in the cytochrome b5 type A ( CYB5A ) and ring finger protein 10 ( RNF10 ) genes associated with body fatness, maximum recorded BMI in childhood and adulthood and T2D .…”

Identification of novel genetic loci GAL3ST4 and CHGB involved in susceptibility to leprosy

“…Whole exome sequencing is a new powerful strategy to discover causative genes in rare Mendelian disorders 12 . Recently, this technology combined with a filtering methodology was demonstrated as an approach to identify susceptible genes among many genetic diseases 13 . Moreover, many genetic variants of common diseases such as diabetes, hypertension and tumor were found by this approach 14 – 16 .…”