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