Type 1 diabetes genome-wide association analysis with imputation identifies five new risk regions

Abstract

Type 1 diabetes genotype datasets have undergone several well powered genome wide analysis studies (GWAS), identifying 57 associated regions at the time of analysis. There are still many regions of smaller effect size or low frequency left to discover, and better exploitation of existing type 1 diabetes cohorts with meta analysis and imputation can precede the acquisition of new or larger cohorts. An existing dataset of 5,913 case and 8,829 control samples was analysed using genome-wide microarrays (Affymetrix GeneChip 500K and Illumina Infinium 550K) with imputation via IMPUTE2 with the 1000 Genomes Project (phase 3) reference panel. Genotyping coverage was doubled in known association regions, and increased by four fold in other regions compared to previous studies. Our analysis resulted in new index variants for 17/57 regions, an expanded set of plausible candidate SNPs for 17 regions, and five novel type 1 diabetes association regions at 1p31.3, 1q24.3, 1q31.2, 2q11.2 and 11q12.2. Candidate genes for the new loci included ITGB3BP, FASLG, RGS1, AFF3 and CD5/CD6. Further prioritisation of causal genes and causal variants will require detailed RNA and protein expression studies, in conjunction with genome annotation studies including analysis of physical promoter-enhancer interactions.