A Human Type 1 Diabetes Susceptibility Locus Maps to Chromosome 21q22.3

  1. Patrick Concannon12,
  2. Suna Onengut-Gumuscu23,
  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 Chen212,
  15. Stephen S. Rich2 and
  16. the Type 1 Diabetes Genetics Consortium
  1. 1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
  2. 2Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
  3. 3Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia
  4. 4Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K
  5. 5Steno Diabetes Center, Gentofte, Denmark
  6. 6Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  7. 7Roche Molecular Systems, Pleasanton, California
  8. 8Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina
  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, Perth, Australia
  11. 11Juvenile Diabetes Research Foundation, New York, New York
  12. 12Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia
  1. Corresponding author: Patrick Concannon, pjc6n{at}virginia.edu

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 families with type 1 diabetes were genotyped with a panel of 6,090 single nucleotide polymorphisms (SNPs). Evidence of association to disease was evaluated by the pedigree disequilibrium test. 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 case and 9,679 control subjects.

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: families with type 1 diabetes (odds ratio [OR] 1.06 [95% CI 1.00–1.11]; P = 0.023) and case and control subjects (1.14 [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 resequencing, genotyping, and functional studies in type 1 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 22 July 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted July 14, 2008.
    • Received June 6, 2008.
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  1. Diabetes vol. 57 no. 10 2858-2861
  1. All Versions of this Article:
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