ArticlemedRxiv : the preprint server for health sciences2025
Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.
Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Obesity is a highly heterogeneous disease that cannot be captured by one single adiposity trait. Here, we performed a multi-trait analysis to study obesity in the context of its common cardiometabolic comorbidities, acknowledging that not all individuals with obesity suffer from cardiometabolic comorbidities and that not all those with normal weight clinically present without them. We leveraged individual-level genotype-phenotype data of 452,768 individuals from the UK Biobank and designed uncoupling phenotypes that are continuous and range from high adiposity with a healthy cardiometabolic profile to low adiposity with an unhealthy cardiometabolic profile. Genome-wide association analyses of these uncoupling phenotypes identified 266 independent variants across 205 genomic loci where the adiposity-increasing allele is also associated with a lower cardiometabolic risk. Consistent with the individual variant effects, a genetic score (GRS
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