期刊
PLOS GENETICS
卷 11, 期 2, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004855
关键词
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资金
- Junior Career Fellowship of the Heidelberg Research Center for Molecular Medicine (HRCMM)
- Career Development Award from Fondation Leducq [12CDA04]
- Transatlantic Networks of Excellence Program from Fondation Leducq [10CVD03]
- European Union [A28]
- Systems Microscopy Network of Excellence [FP7/2007-2013-258068]
- Nationales Genomforschungsnetz-Plus consortium IG-CSG [01GS0865]
- Research Scholar Award from the Massachusetts General Hospital (MGH)
- Donovan Family Foundation
- NIH [R01HL107816]
- Lung GO Sequencing Project [HL-102923]
- WHI Sequencing Project [HL-102924]
- Broad GO Sequencing Project [HL-102925]
- Seattle GO Sequencing Project [HL-102926]
- Heart GO Sequencing Project [HL-103010]
- [RFPS-2007-3-644382]
- [NHGRI 5U54HG003067-11]
A fundamental challenge to contemporary genetics is to distinguish rare missense alleles that disrupt protein functions from the majority of alleles neutral on protein activities. High-throughput experimental tools to securely discriminate between disruptive and non-disruptive missense alleles are currently missing. Here we establish a scalable cell-based strategy to profile the biological effects and likely disease relevance of rare missense variants in vitro. We apply this strategy to systematically characterize missense alleles in the low-density lipoprotein receptor (LDLR) gene identified through exome sequencing of 3,235 individuals and exome-chip profiling of 39,186 individuals. Our strategy reliably identifies disruptive missense alleles, and disruptive-allele carriers have higher plasma LDL-cholesterol (LDL-C). Importantly, considering experimental data refined the risk of rare LDLR allele carriers from 4.5-to 25.3-fold for high LDL-C, and from 2.1-to 20-fold for early-onset myocardial infarction. Our study generates proof-of-concept that systematic functional variant profiling may empower rare variant-association studies by orders of magnitude.
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