Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Metabolic Diseases*/genetics , Genetic Variation*, Humans ; Multifactorial Inheritance/genetics ; Phenotype ; Genetic Predisposition to Disease ; Penetrance ; Exome/genetics ; Heterozygote ; Epistasis, Genetic ; Biological Specimen Banks ; United Kingdom ; Genetic Background

Competing Interests: Competing interests: E.E.K. has received personal fees from Regeneron Pharmaceuticals, 23andMe, Allelica and Illumina; has received research funding from Allelica; and serves on the advisory boards for Encompass Biosciences, Overtone and Galatea Bio. All other authors declare no competing interests.
Over three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (marginal epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai BioMe Biobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable carrier penetrance and disease severity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores modify phenotypes amongst pathogenic carriers and that genetic background additionally alters the effects of pathogenic variants through interactions.
(© 2025. The Author(s).)