Systematic Evaluation Of Genes And Genetic Variants Associated With Type 1 Diabetes Susceptibility

摘要

Genome-wide association studies (GWAS) have found over 60 loci that confer genetic susceptibility to Type 1 diabetes (T1D). Many of these are defined only by anonymous SNPs: the underlying causative genes, and the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. We performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (LD) (r² > 0.8) with the reported SNPs for each locus were tested for commonly occurring non-synonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common non-synonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV- transformed B cell lines (resting and 6h PMA stimulated); purified CD4+ and CD8+ T cells. We mapped cis-acting expression quantitative trait loci (eQTL) and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes.