Advertisement

A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3

  1. Patrick Concannon1,2,
  2. Suna Onengut-Gumuscu2,3,
  3. John A. Todd4,
  4. Deborah J. Smyth4,
  5. Flemming Pociot5,
  6. Regine Bergholdt5,
  7. Beena Akolkar6,
  8. Henry A. Erlich7,
  9. Joan E. Hilner8,
  10. Cécile Julier9,
  11. Grant Morahan10,
  12. Jørn Nerup5,
  13. Concepcion R. Nierras11,
  14. Wei-Min Chen2,12,
  15. Stephen S. Rich2 and
  16. the Type 1 Diabetes Genetics Consortium
  1. 1Department of Biochemistry and Molecular Genetics,
  2. 2Center for Public Health Genomics, and
  3. 3Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia, USA
  4. 4Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  5. 5Steno Diabetes Center, Gentofte, Denmark
  6. 6Division of Diabetes, Endocrinology, and Metabolic Diseases, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD
  7. 7Roche Molecular Systems, Alameda, CA, USA
  8. 8Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA
  9. 9Inserm U730 et CEA, Institut de Génomique Centre National de Génotypage, Evry, France
  10. 10Centre for Diabetes Research, The Western Australian Institute for Medical Research, and Centre for Medical Research, University of Western Australia, Australia
  11. 11Juvenile Diabetes Research Foundation, New York, NY, USA
  12. 12Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA

    Abstract

    Objective. The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled and genotyped a large collection of multiplex families for the purpose of mapping genomic regions linked to type 1 diabetes. In the current study, we tested for evidence of loci associated with type 1 diabetes utilizing genome-wide linkage scan data and family-based association methods.

    Research Design and Methods: A total of 2,496 multiplex type 1 diabetes families were genotyped with a panel of 6,090 SNPs. Evidence of association to disease was evaluated by the pedigree disequilibrium test (PDT). Significant results were followed up by genotyping and analyses in two independent sets of samples: 2,214 parent-affected child trio families and a panel of 7,721 cases and 9,679 controls.

    Results: Three of the SNPs most strongly associated with type 1 diabetes localized to previously identified type 1 diabetes risk loci: INS, IFIH1, and KIAA0350. A fourth strongly associated SNP, rs876498 (P=1.0×10-4) occurred in the sixth intron of the UBASH3A locus at chromosome 21q22.3. Support for this disease association was obtained in two additional independent sample sets, type 1 diabetes families (OR=1.06, 95%CI=1.00-1.11, P=0.023) and cases and controls (OR=1.14, 95%CI=1.09-1.19, P=7.5×10-8).

    Conclusions: The T1DGC 6K SNP scan and follow-up studies reported here confirm previously reported type 1 diabetes associations at INS, IFIH1 and KIAA0350 and identify an additional disease association on chromosome 21q22.3 in the UBASH3A locus (OR=1.10, 95% CI=1.07-1.13, P=4.4×10-12). This gene and its flanking regions are now validated targets for further re-sequencing, genotyping and functional studies in type 1 diabetes.

    Footnotes

      • Received June 6, 2008.
      • Accepted July 14, 2008.

    This Article

    1. Published online before print July 22, 2008, doi: 10.2337/db08-0753 Diabetes July 22, 2008
    1. » Abstract
    2. Full Text (PDF)
    3. All Versions of this Article:
      1. db08-0753v1
      2. 57/10/2858 most recent

    Social Bookmarking

    Current Issue

    1. February 2012, 61 (2)
    1. Current Issue
    1. Alert me to new issues of Diabetes
    Advertisement