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

Abstract

Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of the pancreatic β-cells. Genome-wide association (GWAS) and fine mapping studies have been conducted mainly in European ancestry (EUR) populations. We performed a multi-ancestry GWAS to identify SNPs and HLA alleles associated with T1D risk and age at onset. EUR families (N = 3223), and unrelated individuals of African (AFR, N = 891) and admixed (Hispanic/Latino) ancestry (AMR, N = 308) were genotyped using the Illumina HumanCoreExome BeadArray, with imputation to the TOPMed reference panel. The Multi-Ethnic HLA reference panel was utilized to impute HLA alleles and amino acid residues. Logistic mixed models (T1D risk) and frailty models (age at onset) were used for analysis. In GWAS meta-analysis, seven loci were associated with T1D risk at genome-wide significance: PTPN22, HLA-DQA1, IL2RA, RNLS, INS, IKZF4-RPS26-ERBB3, and SH2B3, with four associated with T1D age at onset (PTPN22, HLA-DQB1, INS, and ERBB3). AFR and AMR meta-analysis revealed NRP1 as associated with T1D risk and age at onset, although NRP1 variants were not associated in EUR ancestry. In contrast, the PTPN22 variant was significantly associated with risk only in EUR ancestry. HLA alleles and haplotypes most significantly associated with T1D risk in AFR and AMR ancestry differed from that seen in EUR ancestry; in addition, the HLA-DRB1*08:02-DQA1*04:01-DQB1*04:02 haplotype was 'protective' in AMR while HLA-DRB1*08:01-DQA1*04:01-DQB1*04:02 haplotype was 'risk' in EUR ancestry, differing only at HLA-DRB1*08. These results suggest that much larger sample sizes in non-EUR populations are required to capture novel loci associated with T1D risk.

Keywords: HLA; genome-wide association study; human genetics; type 1 diabetes.

Figure 1

HLA alleles and amino acids associated with T1D risk in AFR (A), AMR (B), EUR (C) and meta-analysis (D). HLA class I and HLA class II genes are labeled on the x-axis. The y-axis represents −log₁₀(P-value). The horizontal dashed line represents the threshold for genome-wide significance. SNPs are represented by grey diamonds, HLA alleles by yellow diamonds, and HLA amino acids by red diamonds. (A) T1D risk associations within the HLA region in AFR ancestry individuals. (B) T1D risk associations within the HLA region in AMR ancestry individuals. (C) T1D risk associations within the HLA region in EUR ancestry individuals. (D) T1D risk associations within the HLA region in meta-analysis of AFR, AMR and EUR ancestry individuals.

Figure 2

HLA alleles and amino acids associated with T1D age at onset in AFR (A), AMR (B), EUR (C) and meta-analysis (D). HLA class I and HLA class II genes are labeled on the x-axis. The y-axis represents −log₁₀(P-value). The horizontal dashed line represents the threshold for genome-wide significance. SNPs are represented by grey diamonds, HLA alleles by yellow diamonds, and HLA amino acids by red diamonds. (A) T1D age at onset associations within the HLA region in AFR ancestry individuals. (B) T1D age at onset associations within the HLA region in AMR ancestry individuals. (C) T1D age at onset associations within the HLA region in EUR ancestry individuals. (D) T1D age at onset associations within the HLA region in meta-analysis of AFR, AMR and EUR ancestry individuals.

Figure 3

Enrichment of T1D identified genes in other autoimmune diseases. Each bar represents the number of input genes overlapping with the gene set with percentage. Diseases on the x-axis are ordered by increasing P-values. All presented results are significant (adj. P-value < 0.05). P-values were adjusted using a multiple test correction (Benjamini-Hochberg): T1D—4.69 × 10⁻¹⁸, AA—3.62 × 10⁻¹⁶, VIT—6.56 × 10⁻¹⁴, CD—1.54 × 10⁻⁷, PSO—5.96 × 10⁻⁵, CEL—5.79 × 10⁻⁴, JIA—8.23 × 10⁻⁴, RA—5.81 × 10⁻³, SLE—8.79 × 10⁻³, PSC—1.03 × 10⁻², PBC—1.50 × 10⁻², ATD—1.87 × 10⁻². The MHC region (chr6: 25 Mb-35 Mb) was excluded from the analysis. AA—Alopecia Areata, ATD—Autoimmune Thyroid Disease, CEL—Celiac Disease, CD—Crohn’s Disease, JIA—Juvenile Idiopathic Arthritis, PBC—Primary Biliary Cholangitis, PSC—Primary Sclerosing Cholangitis, PSO—Psoriasis (PSO), RA—Rheumatoid Arthritis, SLE—Systemic Lupus Erythematosus, T1D—Type 1 Diabetes, VIT—Vitiligo.