Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Systematic Evaluation Of Genes Associated With Type 1 Diabetes Susceptibility (#109)

Ramesh Ram 1 , Munish Mehta 1 , Quang Nguyen 1 , Irma Larma 1 , Cao Nguyen 1 , Silke Rosinger 2 , Bernhard Boehm 2 , Patrick Concannon 3 , Grant Morahan
  1. Centre for Diabetes Research, Perth, WA, Australia
  2. Endocrinology and Diabetes, Ulm University, Ulm, Germany
  3. Medical Genetics Insititute, University of Florida, Gainesville, USA
Over 60 loci have been reported as associated with Type 1 Diabetes (T1D). Many of these are defined only by anonymous SNPs: identity of the causative genes, and the molecular bases by which they mediate susceptibility, are not known. We performed a systematic analysis to characterize these genes. First, all known genes in modest linkage disequilibrium with the tagging SNP for each locus were tested for commonly occurring non-synonymous variations. We identified common non-synonymous alleles in 112 genes at 37 non-HLA T1D regions. Next, we examined the effect of SNP genotypes on regulating expression levels of nearby (<2Mb) genes (i.e. cis-regulatory effects typical of promoter/enhancer elements). To do so, we examined gene expression in a total of 442 samples of three different cell types: EBV-transformed B cell lines (resting and after PMA stimulation); and purified CD4+ and CD8+ T cells. We mapped cis-acting expression quantitative trait loci (eQTL) and found 35 non-HLA T1D-associated cis-eQTLs that affected the expression of 84 transcripts, typically with P < 5×10−4. Finally, we tested T1D- associated SNPs for trans-regulatory effects (i.e. association with changes in expression of genes located in other chromosomal regions). We found 51 non-HLA T1D-associated trans-eQTLs that significantly affected the expression of 1,162 transcripts with P < 1×10−9. In summary, our systems genetics analyses provide novel insights into the complex genetics of T1D, as well as defining candidate genes for further investigation.