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: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
February 3, 2015
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| In: |
PLoS Genetics
Year: 2015, Volume: 11, Issue: 2 |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1004855 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.pgen.1004855 Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004855 
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| Author Notes: | Aenne S. Thormaehlen, Christian Schuberth, Hong-Hee Won, Peter Blattmann, Brigitte Joggerst-Thomalla, Susanne Theiss, Rosanna Asselta, Stefano Duga, Pier Angelica Merlini, Diego Ardissino, Eric S. Lander, Stacey Gabriel, Daniel J. Rader, Gina M. Peloso, Rainer Pepperkok, Sekar Kathiresan, Heiko Runz |
| Summary: | 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. |
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| Item Description: | Gesehen am 02.07.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1004855 |