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

Abstract

AbstractType 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=3,222), 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<5.0A×10-8) in the meta-analysis of the three ancestry groups:PTPN22,HLA-DQA1,IL2RA,RNLS,INS,IKZF4-RPS26-ERBB3, andSH2B3. Four loci were associated with age at onset (PTPN22,HLA-DQB1,INS, andERBB3). AFR and AMR meta-analysis revealed that theNRP1locus was associated with both risk and age at onset; however, variants withinNRP1were not significantly associated with risk in those of EUR ancestry. In contrast, thePTPN22variant 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 wasHLA-DRB1*03:01-DQA1*05:01-DQB1*02:01differed from theHLA-DRB1*04:01-DQA1*03:01-DQB1*03:02haplotype associated with risk in EUR ancestry. TheHLA-DRB1*08:02-DQA1*04:01-DQB1*04:02haplotype was “protective” in AMR ancestry whileHLA-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.Author SummaryTwin and family studies have shown that genetics play important role in development of type 1 diabetes in childhood. The majority of genetics studies of type 1 diabetes have been performed in populations of European ancestry. Here, we examine the influence of common genetic variants and HLA haplotypes in diverse ancestry samples of type 1 diabetes and earlier age at disease onset. We show thatNRP1region exhibits stronger association with type 1 diabetes risk and age at onset in non-European populations andPTPN22differentiates the risk of type 1 diabetes between individuals of European and non-European ancestries. In addition, we identify protective DR-DQ HLA haplotype in Admixed individuals and DR-DQ HLA haplotype associated with increased risk for type 1 diabetes in European ancestry population. These findings could help improve identification of individuals at high genetic risk of type 1 diabetes and provide opportunities for delay or prevention of type 1 diabetes.