Trans-ancestry meta-analysis of genome-wide association study identifies eight novel genetic loci in type 1 diabetes: A multi-population study.
BACKGROUND Type 1 diabetes (T1D) is a common disease. Although genome-wide association studies (GWASs) have identified hundreds of associated single nucleotide polymorphisms (SNPs), very few T1D GWAS have simultaneously addressed both Asian and European populations. METHODS Here, we conducted a large-scale trans-ancestry meta-analysis including 680,539 European individuals (12,525 T1D cases and 668,014 controls) and 133,251 Asian individuals (1,219 T1D cases and 132,032 controls) to identify genetic associations with T1D. Subsequently, fine-mapping and Summary-data-based Mendelian randomization (SMR) analyses were performed to further refine T1D-related genetic signals. RESULTS We identified 27 T1D-associated loci, including 8 potentially novel loci (near CDKAL1, NRSN1, FAM65B, LRRC16A, TULP1, SLC17A3, LRIG2, C6orf1). Fine-mapping was performed and helped pinpoint 7 putative causal variants (posterior probability, PP > 0.95) with T1D. Among them, rs9366622 (PP = 0.976) and rs1165190 (PP = 0.996) are located near LRRC16A and SLC17A3, respectively. These two variants are the lead SNPs of identified novel loci. SMR analysis identified a putative risk gene (U91328.19) at the novel locus SLC17A3-rs1165190, whose expression level is causally associated with T1D. CONCLUSIONS These findings suggest that, for T1D, increasing ancestral diversity in genetic studies helps identify core genes and provides new insights into pathogenesis.