ArticlePLoS genetics2015
Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed.
- Article
- Putative protective role ofAtherosclerosis plus · 2026Article
- The functional landscape of coding variation in the familial hypercholesterolemia geneScience (New York, N.Y.) · 2026Article
- LDLR variant classification through activity-normalized prime editing screening.bioRxiv : the preprint server for biology · 2025Article
- Characterization of selected LDLR substitutions in patients with familial hypercholesterolemia.Atherosclerosis plus · 2025Article
- Machine learning-based penetrance of genetic variants.Science (New York, N.Y.) · 2025Article
- Large-Scale Functional Characterization of Low-Density Lipoprotein Receptor Gene Variants Improves Risk Assessment in Cardiovascular Disease.JACC. Basic to translational science · 2025Article
- iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia.International journal of molecular sciences · 2024Article
- Analysis of low-density lipoprotein receptor gene mutations in a family with familial hypercholesterolemia.PloS one · 2024Article
- High-Throughput Microscopy Characterization of RareJACC. Basic to translational science · 2023Article
- Novel Tools for Comprehensive Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants.International journal of molecular sciences · 2023Article
- Systematic elucidation of genetic mechanisms underlying cholesterol uptake.Cell genomics · 2023Article
- Calling and Phasing of Single-Nucleotide and Structural Variants of theInternational journal of molecular sciences · 2023Article
- Systematic elucidation of genetic mechanisms underlying cholesterol uptake.bioRxiv : the preprint server for biology · 2023Article
- Rare Variants in Genes of the Cholesterol Pathway Are Present in 60% of Patients with Acute Myocardial Infarction.International journal of molecular sciences · 2022Article
- Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing.International journal of molecular sciences · 2022Article
- AnHGG advances · 2022Article
- The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group.Frontiers in genetics · 2022Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
17 authors.
Funding
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.
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