Genomic and proteomic signatures highlight diverse pathways between obesity and type-2 diabetes

Obesity is a significant risk factor for Type 2 diabetes (T2D), a disease that affects about 10% of the global population. Obesity is also a heterogeneous condition, and the molecular mechanisms linking it to T2D are not yet fully understood. The aim of this study was to elucidate causal pathways between obesity and T2D and to characterize their molecular signatures using an innovative multi-omics approach, thereby highlighting why some, but not all, obese individuals develop T2D. We identified 513 independent obesity-associated SNPs by meta-analysing genome-wide association study data from FinnGen and GIANT (N=699,431). Clustering of Mendelian randomization (MR) estimates, computed using T2D data from DIAGRAM (74,124 cases and 824,006 controls), identified four clusters of SNPs. These clusters, all associated with increased body mass index (BMI), showed differential effects on T2D risk, ranging from harmful to protective. Cluster-specific MR analyses identified 212, out of 2922 protein measurements from the UK Biobank (N=54,219), to be causally affected by any of the clusters. Among these, eight proteins were significantly associated with T2D in downstream MR analyses, representing potential pathways responsible for the heterogeneous link between obesity and T2D. These proteins include, for example, SNAP25, PAM, and FSTL3, suggesting that one of the underlying molecular pathways is tightly linked to insulin synthesis and secretion.