학술논문
Abstract 12730: Whole Genome Sequence Association With Plasma Lipids in 28,541 Individuals.
Document Type
Article
Author
Natarajan, Pradeep; Perry, James; Pampana, Akhil; Broome, Jai G; O'Connell, Jeffrey; Wang, Fei Fei; Khan, Alyna T; Montasser, May; Bielak, Lawrence; Weeks, Daniel; Yanek, Lisa; Peralta, Juan; Aslibekyan, Stella; Allred, Nicholette D; Cade, Brian E; de Vries, Paul S; Bis, Joshua C; Kooperberg, Charles; Wilson, James G; Correa, Adolfo
Source
Subject
*NUCLEOTIDE sequencing
*BLOOD lipids
*LINKAGE disequilibrium
*LIPID analysis
*INDIVIDUALIZED medicine
*CORONARY disease
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Language
ISSN
0009-7322
Abstract
Introduction: Genetic analyses of plasma lipids (total cholesterol, LDL-C, HDL-C, and triglycerides) have yielded fundamental biological, clinical, and therapeutic insights for coronary heart disease (CHD). Hypothesis: Whole genome sequence analysis will facilitate novel associations for plasma lipids. Methods: Deep-coverage (>30X) whole genome sequences were generated as a part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. Plasma lipids were obtained for these individuals. Variants with minor allele count (MAC) > 20 were each individually associated with plasma lipids accounting for age, age2, sex, cohort, genotypically-derived kinship, and prevalent Amish founder mutations in the dataset. Analyses were performed using MMAP and OASIS. Based on prior simulation analyses, we assigned statistical significance if P < 1x10-8. Results: Whole genome sequences and plasma lipids were obtained for 28,541 ethnically-diverse individuals across 14 cohorts (FHS, JHS, Amish, MESA, GENOA, GeneStar, SAS, SAFS, GOLDN, DHS, CFS, WHI, ARIC, CHS) and combined into a single dataset. 35.9M high quality, MAC>20 genomic variants were included. Of observed associations, four novel sites were detected (outside of a +/- 500 kb window of 250 previously reported significant variants). While being just outside of the defined window, the 15q15.3 lead variant, associated with triglycerides, was in strong linkage disequilibrium with a known associated variant. The 9q31.1 lead variant, associated with LDL-C, is a low-frequency (MAF 0.4%) synonymous SNP in RNF20. The 11q14.1 (MAF 0.4%) and 11q23.3 (MAF 0.2%) lead variants were in non-coding sequences and associated with triglycerides. The 11q14.1 variant is near PRCP, whose product is a regulator of energy expenditure and fat mass. The 11q23.3 variant is ~511 kb away from the APOC3-A4-A1 cluster but is not in linkage disequilibrium with previously associated variants. Conclusions: Deep-coverage whole genome sequence association with plasma lipids in 28,541 ethnically-diverse individuals yields putatively novel associations even at sample sizes much smaller than larger array-based genome-wide association analyses. [ABSTRACT FROM AUTHOR]