Fine Mapping and Functional Studies of Risk Variants for Type 1 Diabetes at Chromosome 16p13.13

  1. Suna Onengut-Gumuscu2,3
  1. 1Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA USA;
  2. 2Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA;
  3. 3Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA;
  4. 4Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
  1. Corresponding author: Suna Onengut-Gumuscu, E-mail: so4g{at}


Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13, have been previously associated with risk for several autoimmune diseases including type 1 diabetes. In order to identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we re-sequenced a 455 kb region in type 1 diabetes patients and unaffected controls, identifying 93 novel variants. A panel of 939 SNPs, that included 46 of these novel variants, was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided statistically significant association (P < 5.32 x 10-5) with disease, with rs34306440 (P = 5.74 x 10-6) being most significantly associated. The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease, and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to risk for type 1 diabetes is through reduced expression of DEXI.

  • Received November 26, 2013.
  • Accepted June 26, 2014.

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