Table_5_Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population.xlsx (80.13 kB)
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Table_5_Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population.xlsx

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posted on 02.03.2021, 04:42 authored by Robert W. Read, Karen A. Schlauch, Vincent C. Lombardi, Elizabeth T. Cirulli, Nicole L. Washington, James T. Lu, Joseph J. Grzymski

Clinical conditions correlated with elevated triglyceride levels are well-known: coronary heart disease, hypertension, and diabetes. Underlying genetic and phenotypic mechanisms are not fully understood, partially due to lack of coordinated genotypic-phenotypic data. Here we use a subset of the Healthy Nevada Project, a population of 9,183 sequenced participants with longitudinal electronic health records to examine consequences of altered triglyceride levels. Specifically, Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records to identify: (1) rare and common single-variant genome-wide associations; (2) gene-based associations using a Sequence Kernel Association Test; (3) phenome-wide associations with triglyceride levels; and (4) pleiotropic variants linked to triglyceride levels. The study identified 549 significant single-variant associations (p < 8.75 × 10–9), many in chromosome 11’s triglyceride hotspot: ZPR1, BUD13, APOC3, APOA5. A well-known protective loss-of-function variant in APOC3 (R19X) was associated with a 51% decrease in triglyceride levels in the cohort. Sixteen gene-based triglyceride associations were identified; six of these genes surprisingly did not include a single variant with significant associations. Results at the variant and gene level were validated with the UK Biobank. The combination of a single-variant genome-wide association, a gene-based association method, and phenome wide-association studies identified rare and common variants, genes, and phenotypes associated with elevated triglyceride levels, some of which may have been overlooked with standard approaches.

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