Shared non-HLA genetic architecture across diverse ancestries links insulin secretion and resistance to type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disease with a strong genetic component. Nevertheless, the genetic underpinnings linking type 1 diabetes susceptibility to both insulin secretion and insulin resistance across diverse ancestries have yet to be fully characterised. METHODS: We performed a multi-ancestry type 1 diabetes genome-wide association study meta-analysis comprising 26,198 cases and 36,733 control individuals to identify risk regions across diverse ancestral populations. We further evaluated their associations with clinical traits, integrated epigenetic profiles, mapped candidate genes to define tissue and cell type specificity, and conducted pathway enrichment analyses to elucidate the genetic links between type 1 diabetes and both insulin secretion and insulin resistance. RESULTS: We observed 69 non-HLA regions for type 1 diabetes risk, including three novel genome-wide association study signals: rs2179781 in AHI1 (OR 1.074, p=1.19×10-8), rs10117059 near TRAF1 (OR 1.074, p=3.95×10-8) and rs7184802 near ADCY7 (OR 1.089, p=4.12×10-8). Notably, over one-third (26/69) of these variants were associated with insulin secretion or resistance indices. Using Bayesian fine-mapping integrated with three complementary annotation strategies, we prioritised 136 putative functional variants. Integrative analysis leveraging Roadmap Epigenomics data revealed that these variants exhibited elevated regulatory potential, as evidenced by DNase I hypersensitivity, characteristic H3 histone modifications and active chromatin states in key metabolic tissues (pancreatic islets, liver, skeletal muscle and adipose). Computational mapping and annotation of these variants implicated 447 candidate genes, which showed metabolic tissue-specific expression, and were enriched in pathways related to insulin secretion and resistance (p=5.41×10-4 and 2.10×10-5, respectively), a pattern not evident for HLA risk genes. Subsequent functional characterisation identified ADCY7, regulated by functional variant rs1872691, as the probable causal gene at the novel 16q12.1 locus. In pancreatic beta cells, proinflammatory cytokines downregulated Adcy7 expression and Adcy7 perturbation bidirectionally modulated both insulin secretion and cytokine-induced apoptosis. Conversely, Adcy7 knockdown in adipocytes augmented lipogenesis and enhanced insulin sensitivity. CONCLUSIONS/INTERPRETATION: Our findings support the existence of a shared non-HLA genetic architecture that may link type 1 diabetes susceptibility to both impaired insulin secretion and insulin resistance, providing preliminary genetic evidence for their convergent pathogenic mechanisms.