Follow up analysis of genome-wide association data identifies novel loci for type 1 diabetes
- Struan F.A. Grant1,2,6,
- Hui-Qi Qu8,
- Jonathan P. Bradfield1,
- Luc Marchand8,
- Cecilia E. Kim1,
- Joseph T. Glessner1,
- Rosemarie Grabs8,
- Shayne P. Taback9,
- Edward C. Frackelton1,
- Andrew W. Eckert1,
- Kiran Annaiah1,
- Margaret L. Lawson10,
- F. George Otieno1,
- Erin Santa1,
- Julie L. Shaner1,
- Ryan M. Smith1,
- Robert Skraban1,
- Marcin Imielinski1,
- Rosetta M. Chiavacci1,
- Robert W. Grundmeier3,7,
- Charles A. Stanley4,
- Susan E. Kirsch11,
- Daryl Waggott12,
- Andrew D. Paterson13,
- The DCCT/EDIC Research Group,
- Dimitri S. Monos5,6,
- Constantin Polychronakos (constantin.polychronakos{at}mcgill.ca)8 and
- Hakon Hakonarson (hakonarson{at}chop.edu)1,2,6
- 1Center for Applied Genomics
- 2Division of Human Genetics
- 3Pediatric Research Consortium
- 4Division of Endocrinology and
- 5Department of Pathology and Laboratory Medicine, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
- 6Department of Pediatrics and
- 7Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine University of Pennsylvania, School of Medicine Philadelphia, Pennsylvania 19104, USA
- 8Departments of Pediatrics and Human Genetics, McGill University, Montreal H3H 1P3, Quebec, Canada
- 9Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
- 10Division of Endocrinology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
- 11Markham-Stouffville Hospital, Markham, Ontario, Canada
- 12Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Center for Health Research, Toronto, Ontario, M5G 1X5
- 13Department of Public Health Sciences, Hospital for Sick Kids, University of Toronto, Toronto, Ontario, M5G 1L7
Abstract
Objective: Two recent genome wide association (GWA) studies have revealed novel loci for type 1 diabetes (T1D), a common multifactorial disease with a strong genetic component. To fully utilize the GWA data we had obtained by genotyping 563 T1D probands and 1,146 controls, as well as 483 case-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 SNPs in five novel loci also had P<0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 T1D probands from DCCT/EDIC plus 1,673 controls.
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 (OR = 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 T1D. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.
Footnotes
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- Received July 28, 2008.
- Accepted September 25, 2008.
- Copyright © American Diabetes Association
