Follow-Up Analysis of Genome-Wide Association Data Identifies Novel Loci for Type 1 Diabetes

  1. Hakon Hakonarson1,2,3
  1. 1Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  2. 2Division of Human Genetics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  3. 3Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  4. 4Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada
  5. 5Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
  6. 6Division of Endocrinology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
  7. 7Pediatric Research Consortium, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  8. 8Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  9. 9Division of Endocrinology, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  10. 10Markham-Stouffville Hospital, Markham, Ontario, Canada
  11. 11Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Center for Health Research, Toronto, Ontario, Canada
  12. 12Department of Public Health Sciences, Hospital for Sick Kids, University of Toronto, Toronto, Ontario
  13. 13Department of Pathology and Laboratory Medicine, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  1. Corresponding author: Hakon Hakonarson, hakonarson{at}chop.edu

Abstract

OBJECTIVE—Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject–parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals.

RESEARCH DESIGN AND METHODS—From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects.

RESULTS—Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 × 10−8) and BACH2 (1.13; combined P = 1.25 × 10−6).

CONCLUSIONS—Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 7 October 2008.

  • *A full list of members of the DCCT/EDIC Research Group can be found in the following article: N Engl J Med 356:1842–1852, 2007.

  • S.F.A.G. and H.-Q.Q. contributed equally to this study.

    The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health.

    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.

    • Received July 28, 2008.
    • Accepted September 25, 2008.
| Table of Contents

This Article

  1. Diabetes vol. 58 no. 1 290-295
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db08-1022v1
    2. 58/1/290 most recent