Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions

Angela Wei, Richard Border, Boyang Fu, Sinéad Cullina, Nadav Brandes, Seon-Kyeong Jang, Sriram Sankararaman, Eimear E. Kenny, Miriam S. Udler, Vasilis Ntranos, Noah Zaitlen and Valerie A. Arboleda ()
Additional contact information
Angela Wei: UCLA
Richard Border: UCLA
Boyang Fu: UCLA
Sinéad Cullina: Icahn School of Medicine at Mount Sinai
Nadav Brandes: UCSF
Seon-Kyeong Jang: UCLA
Sriram Sankararaman: UCLA
Eimear E. Kenny: Icahn School of Medicine at Mount Sinai
Miriam S. Udler: Massachusetts General Hospital
Vasilis Ntranos: UCSF
Noah Zaitlen: UCLA
Valerie A. Arboleda: UCLA

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60339-7

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