Trans-ancestry meta-analysis of genome-wide association study identifies eight novel genetic loci in type 1 diabetes:...

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.

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.

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.

These findings suggest that, for T1D, increasing ancestral diversity in genetic studies helps identify core genes and provides new insights into pathogenesis.