Shared non-HLA genetic architecture across diverse ancestries links insulin secretion and resistance to type 1 diabetes
Authors' conclusion
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.
Study context
- Population
- T1D cases and control individuals across diverse ancestral populations
- Participants
- 26,198 vs 36,733
- Comparison
- T1D cases vs controls
- Casesn = 26,198
- Controlsn = 36,733reference
- Outcome
- Non-HLA T1D risk regions
Methodological detailsBayesian fine-mapping, epigenetic integration (Roadmap Epigenomics), pathway enrichment analysis, functional studies in beta cells and adipocytes
- Bayesian fine-mapping
- Epigenetic integration (Roadmap Epigenomics)
- Pathway enrichment analysis
- Functional studies in beta cells and adipocytes
Pooled result
As reported in the abstract
- Non-HLA regions for T1D risk
- 69
- Novel GWAS signal rs2179781 in AHI1
- OR 1.074, p=1.19×10-8
- Novel GWAS signal rs10117059 near TRAF1
- OR 1.074, p=3.95×10-8
- Novel GWAS signal rs7184802 near ADCY7
- OR 1.089, p=4.12×10-8
- Variants associated with insulin secretion or resistance indices
- 26/69
Further pooled results
Fine-mapping and candidate genes
- Putative functional variants prioritised
- 136
- Candidate genes implicated, with metabolic tissue-specific expression
- 447
- Enrichment in insulin secretion pathways
- P = 5.41×10-4
- Enrichment in insulin resistance pathways
- 2.10×10-5
- Variants showed elevated regulatory potential in pancreatic islets, liver, skeletal muscle and adipose
- Pattern not evident for HLA risk genes
Functional characterisation of ADCY7 (16q12.1)
- ADCY7, regulated by functional variant rs1872691, probable causal gene at 16q12.1
- In beta cells, proinflammatory cytokines downregulated Adcy7; Adcy7 perturbation bidirectionally modulated insulin secretion and cytokine-induced apoptosis
- Adcy7 knockdown in adipocytes augmented lipogenesis and enhanced insulin sensitivity
Original publication
Shared non-HLA genetic architecture across diverse ancestries links insulin secretion and resistance to type 1 diabetes. Diabetologia. Published 22 September 2026. doi:10.
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