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

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Exome sequencing has proven powerful to identify protein-coding variation across the human genome, unravel the basis of monogenic diseases and discover rare alleles that confer risk for complex disease. Nevertheless, two key challenges limit its application to complex phenotypes: first, most alleles identified in a population are extremely rare; and second, most alleles are neutral on protein activities. Consequently, association tests that rely on enumerating rare alleles in cases and controls (termed rare variant association studies, RVAS) are typically underpowered, as the many neutral alleles dampen signals that arise from the few alleles that disrupt protein functions. Strategies to securely discriminate disruptive from neutral variants are immature, in particular for missense variants. Here we show that the statistical power of RVAS improves dramatically if variants are stratified according to their in vitro ascertained functions. We establish scalable technology to objectively profile the biological effects of exome-identified missense variants in the low-density lipoprotein receptor (LDLR) through systematic overexpression and complementation experiments in cells. We demonstrate that carriers of LDLR alleles, which our experiments identify as “disruptive-missense”, have higher plasma LDL-C, and that considering in vitro data may make it possible to reduce RVAS sample sizes by more than 2-fold.

Vyšlo v časopise: Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for and Myocardial Infarction. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004855
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004855

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