Population-scale gene-based analysis of whole-genome sequencing provides insights into metabolic health.

ABSTRACT: In addition to its coverage of the noncoding genome, whole-genome sequencing (WGS) may better capture the coding genome than exome sequencing. Here we sought to exploit this and identify new rare, protein-coding variants associated with metabolic health in WGS data (n = 708,956) from the UK Biobank and All of Us studies. Identified genes highlight new biological mechanisms, including protein-truncating variants (PTVs) in the DNA double-strand break repair gene RIF1 that have a substantial effect on body mass index (2.66 kg m^-2, s.e. 0.43, P = 3.7 × 10^-10). UBR3 is an intriguing example where PTVs independently increase body mass index and type 2 diabetes risk. Furthermore, PTVs in IRS2 have a substantial effect on type 2 diabetes (odds ratio 6.4 (3.7-11.3),

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC12513836 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature