MIT Libraries homeMIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction

Author(s)
Thormaehlen, Aenne S.; Schuberth, Christian; Won, Hong-Hee; Blattmann, Peter; Joggerst-Thomalla, Brigitte; Theiss, Susanne; Asselta, Rosanna; Duga, Stefano; Merlini, Piera Angelica; Ardissino, Diego; Lander, Eric S.; Gabriel, Stacey B.; Rader, Daniel J.; Peloso, Gina M.; Pepperkok, Rainer; Kathiresan, Sekar; Runz, Heiko; ... Show more Show less
Thumbnail
Downloadthormaehlen-2015-systematic cell.pdf (1.222Mb)
PUBLISHER_CC

Publisher with Creative Commons License

Creative Commons Attribution

Terms of use
Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/
Metadata
Show full item record
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.
Date issued
2015-02
URI
http://hdl.handle.net/1721.1/94557
Department
Massachusetts Institute of Technology. Department of Biology
Journal
PLOS Genetics
Publisher
Public Library of Science
Citation
Thormaehlen, Aenne S., Christian Schuberth, Hong-Hee Won, Peter Blattmann, Brigitte Joggerst-Thomalla, Susanne Theiss, Rosanna Asselta, et al. “Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction.” Edited by Chris Cotsapas. PLoS Genet 11, no. 2 (February 3, 2015): e1004855.
Version: Final published version
ISSN
1553-7404
1553-7390

Collections
  • MIT Open Access Articles

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries homeMIT Libraries logo

Find us on

Twitter Facebook Instagram YouTube RSS

MIT Libraries navigation

SearchHours & locationsBorrow & requestResearch supportAbout us
PrivacyPermissionsAccessibility
MIT
Massachusetts Institute of Technology
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.