A multi-ancestry genome-wide association study in type 1 diabetes

Abstract

Type 1 diabetes is a chronic autoimmune disease caused by destruction of the pancreatic β-cells. Genome-wide association (GWAS) and fine mapping studies associated with type 1 diabetes are mainly in European ancestry populations. We conducted a multi-ancestry GWAS to identify single nucleotide polymorphisms (SNPs) and HLA alleles associated with type 1 diabetes risk and age at onset. The Type 1 Diabetes Genetics Consortium (T1DGC) samples were genotyped using the Illumina CoreExome BeadChip array, and included families of largely European ancestry (EUR, N=3,223), unrelated individuals of African ancestry (AFR, N=891) and admixed (primarily Hispanic/Latino) ancestry (AMR, N=308). The four-digit multi-ancestry HLA reference panel (HLA-TAPAS) was used to impute HLA alleles. Logistic mixed models were used for analysis of genetic data with type 1 diabetes risk, while frailty models were used for analysis of age at onset. Seven loci were associated with type 1 diabetes at genome-wide significance (P<5.0x10-8) in the meta-analysis of the three ancestry groups: PTPN22, HLA-DQA1, IL2RA, RNLS, INS, IKZF4-RPS26-ERBB3, and SH2B3. Four loci were associated with age at onset (PTPN22, HLA-DQB1, INS, and ERBB3). AFR and AMR meta-analysis revealed that the NRP1 locus was associated with both risk and age at onset; however, variants within NRP1 were not significantly associated with risk in those of EUR ancestry. In contrast, the PTPN22 variant rs2476601 (R620W) was significantly associated with risk only in EUR ancestry individuals. The HLA haplotype most significantly associated with risk in AFR and AMR ancestry was HLA-DRB1*03:01-DQA1*05:01-DQB1*02:01 differed from the HLA-DRB1*04:01-DQA1*03:01-DQB1*03:02 haplotype associated with risk in EUR ancestry. The HLA-DRB1*08:02-DQA1*04:01-DQB1*04:02 haplotype was protective in AMR ancestry while HLA-DRB1*08:01-DQA1*04:01-DQB1*04:02 (differing only at DRB1) was risk in EUR ancestry. The multi-ancestry GWAS enabled identification of ancestry-specific genetic variants, HLA alleles and haplotypes that are associated with type 1 diabetes risk and age at onset.