title: Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.
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.
authors: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/ EMBL, Heidelberg, Germany.
authors: Aenne S
authors: AS
authors: Thormaehlen
authors: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/ EMBL, Heidelberg, Germany.
authors: Christian
authors: C
authors: Schuberth
authors: Center of Human Genetic Research (CHGR), Massachusetts General Hospital, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Hong-Hee
authors: HH
authors: Won
authors: Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/ EMBL, Heidelberg, Germany; Cell Biology/Biophysics Unit, European Molecular Biological Laboratory, Heidelberg, Germany.
authors: Peter
authors: P
authors: Blattmann
authors: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/ EMBL, Heidelberg, Germany.
authors: Brigitte
authors: B
authors: Joggerst-Thomalla
authors: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors: Susanne
authors: S
authors: Theiss
authors: Humanitas University, Milan, Italy.
authors: Rosanna
authors: R
authors: Asselta
authors: Humanitas University, Milan, Italy.
authors: Stefano
authors: S
authors: Duga
authors: Division of Cardiology, Ospedale Niguarda, Milan, Italy.
authors: Pier Angelica
authors: PA
authors: Merlini
authors: Department of Cardiology, Parma Hospital, Parma, Italy.
authors: Diego
authors: D
authors: Ardissino
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Eric S
authors: ES
authors: Lander
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Stacey
authors: S
authors: Gabriel
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Daniel J
authors: DJ
authors: Rader
authors: Center of Human Genetic Research (CHGR), Massachusetts General Hospital, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Gina M
authors: GM
authors: Peloso
authors: Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/ EMBL, Heidelberg, Germany; Cell Biology/Biophysics Unit, European Molecular Biological Laboratory, Heidelberg, Germany.
authors: Rainer
authors: R
authors: Pepperkok
authors: Center of Human Genetic Research (CHGR), Massachusetts General Hospital, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Division of Cardiology, Ospedale Niguarda, Milan, Italy.
authors: Sekar
authors: S
authors: Kathiresan
authors: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/ EMBL, Heidelberg, Germany; Center of Human Genetic Research (CHGR), Massachusetts General Hospital, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Heiko
authors: H
authors: Runz
mesh_terms: D000483:Alleles; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D059472:Exome / Q000235:genetics*; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D008078:Cholesterol, LDL; D011973:Receptors, LDL
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