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

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

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 c...

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Main Authors: Thormaehlen, 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, Heiko
Format: Online
Language:English
Published: Public Library of Science 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409815/
id pubmed-4409815
recordtype oai_dc
spelling pubmed-44098152015-05-12 Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction Thormaehlen, 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, Heiko Research Article 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. Public Library of Science 2015-02-03 /pmc/articles/PMC4409815/ /pubmed/25647241 http://dx.doi.org/10.1371/journal.pgen.1004855 Text en © 2015 Thormaehlen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Thormaehlen, 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, Heiko
spellingShingle Thormaehlen, 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, Heiko
Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction
author_facet Thormaehlen, 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, Heiko
author_sort Thormaehlen, Aenne S.
title Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction
title_short Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction
title_full Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction
title_fullStr Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction
title_full_unstemmed Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction
title_sort systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for ldlr and myocardial infarction
description 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.
publisher Public Library of Science
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409815/
_version_ 1613215677607313408

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