HLA-focused type 1 diabetes genetic risk prediction in populations of diverse ancestry

Type 1 diabetes is characterised by the destruction of pancreatic beta cells. Genetic factors account for approximately 50% of the total risk, with variants in the HLA region contributing to half of this genetic risk. Research has historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRS_HLA) using SNPs or HLA alleles from four ancestry groups (admixed African [AFR; T1D GRS_HLA-AFR], admixed American [AMR; T1D GRS_HLA-AMR], European [EUR; T1D GRS_HLA-EUR] and Finnish [FIN; T1D GRS_HLA-FIN]). We also developed an across-ancestry GRS (ALL; T1D GRS_HLA-ALL). We assessed the performance of the GRS in each population to determine the transferability of constructed scores.

A total of 41,689 samples and 13,695 SNPs in the HLA region were genotyped, with HLA alleles imputed using the HLA-TAPAS multi-ethnic reference panel. Conditionally independent SNPs and HLA alleles associated with type 1 diabetes were identified in each population group to construct T1D GRS_HLA models. Generated T1D GRS_HLA models were used to predict HLA-focused type 1 diabetes genetic risk across four ancestry groups. The performance of each T1D GRS_HLA model was assessed using receiver operating characteristic (ROC) AUCs, and compared statistically.

Each T1D GRS_HLA model included a different number of conditionally independent HLA-region SNPs (AFR, n=5; AMR, n=3; EUR, n=38; FIN, n=6; ALL, n=36) and HLA alleles (AFR, n=6; AMR, n=5; EUR, n=40; FIN, n=8; ALL, n=41). The ROC AUC values for the T1D GRS_HLA from SNPs or HLA alleles were similar, and ranged from 0.73 (T1D GRS_{HLA-allele-AMR} applied to FIN) to 0.88 (T1D GRS_{HLA-allele-EUR} applied to EUR). The ROC AUC using the combined set of conditionally independent SNPs (T1D GRS_HLA-SNP-ALL) or HLA alleles (T1D GRS_{HLA-allele-ALL}) performed uniformly well across all ancestry groups, with values ranging from 0.82 to 0.88 for SNPs and 0.80 to 0.87 for HLA alleles.

T1D GRS_HLA models derived from SNPs performed equivalently to those derived from HLA alleles across ancestries. In addition, T1D GRS_HLA-SNP-ALL and GRS_{HLA-allele-ALL} models had consistently high ROC AUC values when applied across ancestry groups. Larger studies in more diverse populations are needed to better assess the transferability of T1D GRS_HLA across ancestries.