Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.
PLoS Genet
; 11(2): e1004855, 2015 Feb.
Article
in En
| MEDLINE
| ID: mdl-25647241
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, LDL
/
Genetic Association Studies
/
Exome
/
Myocardial Infarction
Type of study:
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
PLoS Genet
Journal subject:
GENETICA
Year:
2015
Document type:
Article
Affiliation country:
Country of publication: