Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.

ABSTRACT: Obesity is a heterogeneous condition not adequately captured by a single adiposity trait. We conducted a multi-trait genome-wide association analysis using individual-level data from 452,768 UK Biobank participants to study obesity in relation to cardiometabolic health. We defined continuous 'uncoupling phenotypes', ranging from high adiposity with healthy cardiometabolic profiles to low adiposity with unhealthy ones. We identified 266 variants across 205 genomic loci where adiposity-increasing alleles were simultaneously associated with lower cardiometabolic risk. A genetic risk score (GRS_uncoupling) aggregating these variants was associated with a lower risk of cardiometabolic disorders, including dyslipidemia and ischemic heart disease, despite higher obesity risk; unlike an

SUBMITTER: Chami N 

PROVIDER: S-EPMC12618246 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature