Abstract Aims/hypothesis 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. Methods 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. Results 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. Conclusions/interpretation 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. Graphical Abstract
Michałek et al. (2025) studied this question.