Genetic and molecular signatures highlight diverse pathways linking obesity to type 2 diabetes

Obesity is a major risk factor for type 2 diabetes, a disease affecting approximately 10% of the global population. Obesity is a heterogeneous condition, with different components exerting distinct, and sometimes opposing, effects on type 2 diabetes risk. Here, we aim to identify molecular mechanisms through which distinct components of obesity influence risk for type 2 diabetes by integrating multi-omics data. We identify SNPs associated with body mass index in males and females and cluster them based on their Mendelian randomisation estimates on type 2 diabetes risk. This analysis reveals four SNP clusters with distinct effects on type 2 diabetes ranging from strongly harmful to protective. We perform cluster-specific two-sample Mendelian randomisation analyses across over 3000 molecular traits to delineate metabolic, lipid, endocrine and glycaemic pathways mediating the harmful and protective effects of distinct obesity components on type 2 diabetes risk.