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

Pradeep Natarajan, Gina M. Peloso, Seyedeh Maryam Zekavat, May Montasser, Andrea Ganna, Mark Chaffin, Amit V. Khera, Wei Zhou, Jonathan M. Bloom, Jesse M. Engreitz, Jason Ernst, Jeffrey R. O’Connell, Sanni E. Ruotsalainen, Maris Alver, Ani Manichaikul, W. Craig Johnson, James A. Perry, Timothy Poterba, Cotton Seed, Ida L. Surakka, Tonu Esko, Samuli Ripatti, Veikko Salomaa, Adolfo Correa, Ramachandran S. Vasan, Manolis Kellis, Benjamin M. Neale, Eric S. Lander, Goncalo Abecasis, Braxton Mitchell, Stephen S. Rich, James G. Wilson, L. Adrienne Cupples, Jerome I. Rotter, Cristen J. Willer and Sekar Kathiresan ()
Additional contact information
Pradeep Natarajan: Massachusetts General Hospital
Gina M. Peloso: Boston University School of Public Health
Seyedeh Maryam Zekavat: Broad Institute of Harvard & MIT
May Montasser: University of Maryland
Andrea Ganna: Broad Institute of Harvard & MIT
Mark Chaffin: Broad Institute of Harvard & MIT
Amit V. Khera: Massachusetts General Hospital
Wei Zhou: University of Michigan
Jonathan M. Bloom: Broad Institute of Harvard & MIT
Jesse M. Engreitz: Broad Institute of Harvard & MIT
Jason Ernst: University of California, Los Angeles
Jeffrey R. O’Connell: University of Maryland
Sanni E. Ruotsalainen: Institute for Molecular Medicine Finland
Maris Alver: University of Tartu
Ani Manichaikul: University of Virginia
W. Craig Johnson: University of Washington
James A. Perry: University of Maryland
Timothy Poterba: Broad Institute of Harvard & MIT
Cotton Seed: Broad Institute of Harvard & MIT
Ida L. Surakka: Institute for Molecular Medicine Finland
Tonu Esko: University of Tartu
Samuli Ripatti: Institute for Molecular Medicine Finland
Veikko Salomaa: Institute for Molecular Medicine Finland
Adolfo Correa: University of Mississippi Medical Center
Ramachandran S. Vasan: Boston University School of Medicine
Manolis Kellis: Broad Institute of Harvard & MIT
Benjamin M. Neale: Massachusetts General Hospital
Eric S. Lander: Broad Institute of Harvard & MIT
Goncalo Abecasis: University of Michigan
Braxton Mitchell: University of Maryland
Stephen S. Rich: University of Virginia
James G. Wilson: University of Mississippi Medical Center
L. Adrienne Cupples: Boston University School of Public Health
Jerome I. Rotter: Harbor-UCLA Medical Center
Cristen J. Willer: University of Michigan
Sekar Kathiresan: Massachusetts General Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05747-8

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