| Title: | Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population |
| Journal: | Frontiers in Genetics |
| Published: | 2 Mar 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33763119/ |
| DOI: | https://doi.org/10.3389/fgene.2021.639418 |
| URL: | https://www.frontiersin.org/articles/10.3389/fgene.2021.639418/pdf |
| Citations: | 9 (3 in last 2 years) as of 8 Aug 2024 |
Publication 5061
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Abstract
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.</p>
7 Authors
- Robert W. Read
- Karen A. Schlauch
- Vincent C. Lombardi
- Elizabeth T. Cirulli
- Nicole L. Washington
- James T. Lu
- Joseph J. Grzymski
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