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dc.contributor.authorThormaehlen, Aenne S.
dc.contributor.authorSchuberth, Christian
dc.contributor.authorWon, Hong-Hee
dc.contributor.authorBlattmann, Peter
dc.contributor.authorJoggerst-Thomalla, Brigitte
dc.contributor.authorTheiss, Susanne
dc.contributor.authorAsselta, Rosanna
dc.contributor.authorDuga, Stefano
dc.contributor.authorMerlini, Piera Angelica
dc.contributor.authorArdissino, Diego
dc.contributor.authorLander, Eric S.
dc.contributor.authorGabriel, Stacey B.
dc.contributor.authorRader, Daniel J.
dc.contributor.authorPeloso, Gina M.
dc.contributor.authorPepperkok, Rainer
dc.contributor.authorKathiresan, Sekar
dc.contributor.authorRunz, Heiko
dc.date.accessioned2015-02-17T16:00:40Z
dc.date.available2015-02-17T16:00:40Z
dc.date.issued2015-02
dc.date.submitted2014-07
dc.identifier.issn1553-7404
dc.identifier.issn1553-7390
dc.identifier.urihttp://hdl.handle.net/1721.1/94557
dc.description.abstractA 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.en_US
dc.description.sponsorshipNational Heart, Lung, and Blood Institute. Go Exome Sequencing Project (Lung GO Sequencing Project. HL-102923)en_US
dc.description.sponsorshipNational Heart, Lung, and Blood Institute. Go Exome Sequencing Project (WHI Sequencing Project. HL-102924)en_US
dc.description.sponsorshipNational Heart, Lung, and Blood Institute. Go Exome Sequencing Project (Broad GO Sequencing Project. HL-102925)en_US
dc.description.sponsorshipNational Heart, Lung, and Blood Institute. Go Exome Sequencing Project (Seattle GO Sequencing Project. HL-102926)en_US
dc.description.sponsorshipNational Heart, Lung, and Blood Institute. Go Exome Sequencing Project (Heart GO Sequencing Project. HL-103010)en_US
dc.description.sponsorshipCHARGE Lipids Working Group (HL-105756)en_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pgen.1004855en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourcePublic Library of Scienceen_US
dc.titleSystematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarctionen_US
dc.typeArticleen_US
dc.identifier.citationThormaehlen, 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.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorLander, Eric S.en_US
dc.relation.journalPLOS Geneticsen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsThormaehlen, Aenne S.; Schuberth, Christian; Won, Hong-Hee; Blattmann, Peter; Joggerst-Thomalla, Brigitte; Theiss, Susanne; Asselta, Rosanna; Duga, Stefano; Merlini, Pier Angelica; Ardissino, Diego; Lander, Eric S.; Gabriel, Stacey; Rader, Daniel J.; Peloso, Gina M.; Pepperkok, Rainer; Kathiresan, Sekar; Runz, Heikoen_US
mit.licensePUBLISHER_CCen_US


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