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

Objective

Over 10% of type 1 diabetes (T1D) cases do not have high-risk HLA-DR3 or DR4 haplotypes with distinct clinical features such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals.

Research Design and Methods

We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. We next performed heterogeneity tests to examine differences in T1D risk variants in non-DR3/DR4 compared to DR3/DR4 individuals. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between non-DR3/DR4 and DR3/DR4. Finally, we developed a genetic risk score (GRS) to predict T1D in non-DR3/DR4 individuals and compared to existing T1D GRS.

Results

We identified 18 T1D risk variants in non-DR3/DR4 samples. Risk variants at the MHC and multiple other loci genome-wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-assocated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and beta cells, and depleted in T-cells, compared to DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from non-diabetes (AUC=0.867, p=7.48x10-32) and T2D (AUC=0.907, p=4.94x10-44).

Conclusions

In total we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype which uncovered disease mechanisms and enabled more accurate prediction of T1D across HLA background.