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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Natarajan, P; Peloso, GM; Zekavat, SM; Montasser, M; Ganna, A; Chaffin, M; Khera, AV; Zhou, W; Bloom, JM; Engreitz, JM; Ernst, J; O'Connell, JR; Ruotsalainen, SE; Alver, M; Manichaikul, A; Johnson, WC; Perry, JA; Poterba, T; Seed, C; Surakka, IL; Esko, T; Ripatti, S; Salomaa, V; Correa, A; Vasan, RS; Kellis, M; Neale, BM; Lander, ES; Abecasis, G; Mitchell, B; Rich, SS; Wilson, JG; Cupples, LA; Rotter, JI; Willer, CJ; Kathiresan, S; NHLBI TOPMed Lipids Working Group,

Published Date

  • August 23, 2018

Published In

Volume / Issue

  • 9 / 1

Start / End Page

  • 3391 -

PubMed ID

  • 30140000

Pubmed Central ID

  • PMC6107638

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-05747-8


  • eng

Conference Location

  • England