Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

NHLBI TOPMed Lipids Working Group

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50 Scopus citations

Abstract

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

Original languageEnglish (US)
Article number3391
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
WGS for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study” (phs000974.v1.p1) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964.v1.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: Genetics of Cardiometa-bolic Health in the Amish” (phs000956.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Further study-specific acknowledgements can be found in Supplementary Note 2. This analysis was supported by the American Heart Association 17SDG33680041 (P.N.), the National, Heart, Lung, and Blood Institute of the US National Institutes of Health grants K01 HL125751 (G.M.P.), R01 HL127564 (C.W. and S.K.), and TOPMed analysis support grant (G.M.P. and P.N.), the Ofer and Shelly Nemirovsky Research Scholar award from Massachusetts General Hospital (S.K.), and the Donovan Family Foundation (S.K.). The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Publisher Copyright:
© 2018, The Author(s).

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