Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction

Aenne S. Thormaehlen, Christian Schuberth, Hong Hee Won, Peter Blattmann, Brigitte Joggerst-Thomalla, Susanne Theiss, Rosanna Asselta, Stefano Duga, Pier A ngelica Merlini, Diego Ardissino, Eric S. Lander, Stacey Gabriel, Daniel J. Rader, Gina M. Peloso, Rainer Pepperkok, Sekar Kathiresan, Heiko Runz

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)e1004855
JournalPLoS Genetics
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Thormaehlen, A. S., Schuberth, C., Won, H. H., Blattmann, P., Joggerst-Thomalla, B., Theiss, S., Asselta, R., Duga, S., Merlini, P. A. N., Ardissino, D., Lander, E. S., Gabriel, S., Rader, D. J., Peloso, G. M., Pepperkok, R., Kathiresan, S., & Runz, H. (2015). Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. PLoS Genetics, 11(2), e1004855. https://doi.org/10.1371/journal.pgen.1004855