Genetic discovery and risk prediction for type 1 diabetes in individuals without high-risk HLA-DR3/DR4 haplotypes

Over 10% of individuals with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes, and whether they carry distinct genetic risk is unknown. To identify genetic drivers of T1D in the absence of DR3/DR4, we performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. We identified risk variants at the MHC locus and genome-wide with evidence for heterogeneity in effects on T1D compared to DR3/DR4. T1D-associated variants in non-DR3/DR4 individuals were enriched for loci, regulatory elements, and pathways related to antigen presentation, innate immunity, and beta cells, and depleted in T cells, compared to DR3/DR4. Most non-DR3/DR4 T1D cases are poorly classified based on the existing T1D GRS2, and we created a new GRS which highly discriminated non-DR3/DR4 T1D from non-diabetes and T2D and outperformed GRS2. In total we identified heterogeneity in T1D genetic risk dependent on high-risk HLA haplotype which revealed distinct disease mechanisms and enabled more accurate risk prediction for T1D a non-DR3/DR4 background.