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

Aims/hypothesis: Type 1 diabetes is characterized by the destruction of pancreatic beta cells. Genetic factors account for ~50% of the total risk, with variants in the Human Leukocyte Antigen (HLA) region contributing to half of this genetic risk, with research historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRS_HLA) utilizing single nucleotide polymorphisms (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), Finnish (FIN; T1D GRS_HLA-FIN) and across ancestry (ALL; T1D GRS_HLA-ALL). We assessed the performance of genetic risk scores in each population to determine 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. Performance of each T1D GRS_HLA model was assessed using Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) 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 of 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} 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, 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.