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

Dense genotyping of autoimmune regions identifies 3 novel T1D risk loci as well as causative genes and variants at previously reported sites. (#16)

Pat Concannon 1 , Stephen S. Rich 2 3 , Suna Onengut-Gumuscu 2 4 , Wei-Min Chen 2 3 , Aaron R. Quinlan 2 3 , Type One Diabetes Genetics Consortium 2
  1. Genetics Institute, University of Florida, Gainesville, FL, United States
  2. Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA
  3. Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA
  4. Department of Medicine, Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA, USA
Genome-wide association studies of type 1 diabetes (T1D) have reported numerous new T1D risk loci.  These loci now require detailed mapping to identify candidate genes and causal variants for functional studies. We used ImmunoChip, a custom high density genotyping array, to genotype 16,086 T1D case and control samples and 2,670 families for 154,939 single nucleotide polymorphisms (SNPs) from 186 loci previously implicated in autoimmunity.  Of previously reported non-MHC T1D associated regions, 36 were replicated (P ≤ 3.23 × 10-7) with most (29/36) attaining genome-wide significance (P ≤ 5 x 10-8). Three novel T1D loci were identified: 1q32.1, containing CAMSAP2, GPR25 and C1orf106; 4q32.3, between CPE and TLL1; and 10p11.22, a region 3´ of NRP1, and 5´ of ITGB1.  A hypothesis testing procedure was performed to determine which SNPs in each non-MHC locus were likely to be causal.  Of 16,991 candidate SNPs tested, the causal variant hypothesis was not rejected for 388 SNPs.  The positions of these SNPs suggested possible roles in disease pathogenesis.  For 27 of the 39 T1D-associated loci, the most significant SNP was located within the transcription unit of a gene. For four loci, the most associated SNP is a non-synonymous coding variant.  For 3 more loci, the most associated SNP was in a non-coding RNA.  A majority of the putative causal SNPs overlapped promoter histone marks, enhancer histone marks, DNase I sensitive sites, predicted protein binding sites or other motifs  compiled in ENCODE.  In summary, ImmunoChip genotyping has clarified the complex genetic risk in T1D, identifying putative causal genes. These genes are located in both previously disease-associated loci and in 3 novel T1D risk loci.  Despite the tissue-specific autoimmune response that characterizes T1D, the majority of T1D risk variants localize in or near genes whose products act upon the immune system, rather than the target organ.