期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05747-8
关键词
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资金
- National Heart, Lung and Blood Institute (NHLBI)
- American Heart Association [17SDG33680041]
- National, Heart, Lung, and Blood Institute of the US National Institutes of Health [K01 HL125751, R01 HL127564]
- Massachusetts General Hospital
- Donovan Family Foundation
- TOPMed analysis support grant
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [KL2TR001100] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL121007, R01HL112064, R01HL127564, K01HL130609, K08HL140203, R01HL138737, R01HL142711, K01HL136700, R01HL117626, K01HL125751, T32HL139439, R01HL120393] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG003067, R01HG002898] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK075787] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U54GM115428, T32GM007205] Funding Source: NIH RePORTER
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(similar to 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.
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