|
|
|
|
Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction
|
|
|
|
|
|
|
|
نویسنده
|
thormaehlen a.s. ,schuberth c. ,won h.-h. ,blattmann p. ,joggerst-thomalla b. ,theiss s. ,asselta r. ,duga s. ,merlini p.a. ,ardissino d. ,lander e.s. ,gabriel s. ,rader d.j. ,peloso g.m. ,pepperkok r. ,kathiresan s. ,runz h.
|
|
منبع
|
plos genetics - 2015 - دوره : 11 - شماره : 2 - صفحه:1 -23
|
|
چکیده
|
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. © 2015 thormaehlen et al.
|
|
|
|
|
آدرس
|
institute of human genetics,university of heidelberg,heidelberg,germany,molecular medicine partnership unit (mmpu),university of heidelberg/ embl,heidelberg, Germany, institute of human genetics,university of heidelberg,heidelberg,germany,molecular medicine partnership unit (mmpu),university of heidelberg/ embl,heidelberg, Germany, center of human genetic research (chgr),massachusetts general hospital,bostonma,united states,broad institute of mit and harvard,cambridge,ma,united states,cardiovascular research center,massachusetts general hospital,boston,ma,united states,department of medicine,harvard medical school,boston,ma, United States, molecular medicine partnership unit (mmpu),university of heidelberg/ embl,heidelberg,germany,cell biology/biophysics unit,european molecular biological laboratory,heidelberg, Germany, institute of human genetics,university of heidelberg,heidelberg,germany,molecular medicine partnership unit (mmpu),university of heidelberg/ embl,heidelberg, Germany, institute of human genetics,university of heidelberg,heidelberg, Germany, humanitas university,milan, Italy, humanitas university,milan, Italy, division of cardiology,ospedale niguarda,milan, Italy, department of cardiology,parma hospital,parma, Italy, broad institute of mit and harvard,cambridge,ma, United States, broad institute of mit and harvard,cambridge,ma, United States, perelman school of medicine,university of pennsylvania,philadelphia,pa, United States, center of human genetic research (chgr),massachusetts general hospital,bostonma,united states,broad institute of mit and harvard,cambridge,ma, United States, molecular medicine partnership unit (mmpu),university of heidelberg/ embl,heidelberg,germany,cell biology/biophysics unit,european molecular biological laboratory,heidelberg, Germany, center of human genetic research (chgr),massachusetts general hospital,bostonma,united states,broad institute of mit and harvard,cambridge,ma,united states,cardiovascular research center,massachusetts general hospital,boston,ma,united states,division of cardiology,ospedale niguarda,milan, Italy, institute of human genetics,university of heidelberg,heidelberg,germany,molecular medicine partnership unit (mmpu),university of heidelberg/ embl,heidelberg,germany,center of human genetic research (chgr),massachusetts general hospital,bostonma,united states,broad institute of mit and harvard,cambridge,ma, United States
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|