Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.

PLoS Genet
Authors
Keywords
Abstract

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.

Year of Publication
2015
Journal
PLoS Genet
Volume
11
Issue
2
Pages
e1004855
Date Published
2015 Feb
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1004855
PubMed ID
25647241
PubMed Central ID
PMC4409815
Links
Grant list
HL-103010 / HL / NHLBI NIH HHS / United States
R01HL107816 / HL / NHLBI NIH HHS / United States
R21 HL120781 / HL / NHLBI NIH HHS / United States
HL-102924 / HL / NHLBI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
HL-102926 / HL / NHLBI NIH HHS / United States
5U54HG003067-11 / HG / NHGRI NIH HHS / United States
HL-102925 / HL / NHLBI NIH HHS / United States
HL-105756 / HL / NHLBI NIH HHS / United States
HL-102923 / HL / NHLBI NIH HHS / United States