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

Authors :
Wei A
Border R
Fu B
Cullina S
Brandes N
Jang SK
Sankararaman S
Kenny E
Udler MS
Ntranos V
Zaitlen N
Arboleda V
Source :
MedRxiv : the preprint server for health sciences [medRxiv] 2024 May 01. Date of Electronic Publication: 2024 May 01.
Publication Year :
2024

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 predicted phenotypes amongst pathogenic carriers and that epistatic effects can exceed main carrier effects by an order of magnitude.

Details

Language :
English
Database :
MEDLINE
Journal :
MedRxiv : the preprint server for health sciences
Accession number :
37745486
Full Text :
https://doi.org/10.1101/2023.09.14.23295564