Faculty Collaboration Database

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat Commun 2018 Aug 23;9(1):3391

Date

08/25/2018

Pubmed ID

30140000

Pubmed Central ID

PMC6107638

DOI

10.1038/s41467-018-05747-8

Scopus ID

2-s2.0-85052245414 (requires institutional sign-in at Scopus site)   132 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.

Author List

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

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Base Sequence
Cholesterol, LDL
Gene Frequency
Genome, Human
Genome-Wide Association Study
High-Throughput Nucleotide Sequencing
Humans
Lipids
Models, Genetic
Mutation