Ancestry-specific TWAS refines type 2 diabetes GWAS loci in disease-relevant tissues

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by hyperglycemia and insulin resistance. Although genome-wide association studies (GWAS) have identified >600 T2D risk loci, the causal genes and the relevant tissues mediating these associations remain largely unresolved. To address this challenge, we performed tissue-specific, ancestry-aware transcriptome-wide association studies (TWAS) across six T2D-relevant tissues: subcutaneous adipose, visceral adipose, brain hypothalamus, liver, skeletal muscle, and pancreas. We conducted ancestry-specific multi-tissue TWAS in European ancestry (EUR) data using summary statistics from the largest EUR GWAS (242,283 cases and 1,569,734 controls) and pre-trained gene expression prediction models derived from 689 EUR individuals from the Genotype-Tissue Expression (GTEx) Project. Conditional analyses were performed to identify independent TWAS signals. We identified 684-750 significant gene-T2D associations per tissue (P < 1.919 x 10-6), implicating both established and novel candidate genes. Among these, JAZF1 and IDE showed consistent association signals across all six tissues, whereas TCF7L2 and WSF1 exhibited heterogeneous effects restricted to a subset of T2D-relevant tissues. Conditional analyses further refined these signals to 289-322 independent TWAS signals per tissue. Together, these finding highlight substantial regulatory heterogeneity in the genetic architecture of T2D and underscore the importance of tissue context in interpreting disease-associated loci. Cross-ancestry replication of EUR-derived TWAS signals was evaluated in African American (AFA) individuals. We conducted an AFA-TWAS using summary statistics from the largest AFA GWAS (50,251 cases and 103,909 controls) in combination with gene expression prediction models trained in 111 AFA individuals from GTEx. We observed significant enrichment of EUR-derived T2D TWAS signals in the AFA TWAS across subcutaneous adipose, visceral adipose, skeletal muscle, and pancreas, whilst enrichment was weaker in liver, likely reflecting limited sample size. Overall, our findings demonstrate that integrating tissue-specific and ancestry-aware TWAS refines the identification of causal genes for T2D, with cross-ancestry replication supporting the robustness of these signals and cross-tissue analyses revealing context-specific effects. However, they also highlight the limited availability of non-EUR datasets and the need for larger, more diverse ancestry-specific transcriptomic resources.