Follow-Up Analysis of Genome-Wide Association Data Identifies Novel Loci for Type 1 Diabetes
Struan F.A. Grant 1 2 3 ,
Hui-Qi Qu 4 ,
Jonathan P. Bradfield 1 ,
Luc Marchand 4 ,
Cecilia E. Kim 1 ,
Joseph T. Glessner 1 ,
Rosemarie Grabs 4 ,
Shayne P. Taback 5 ,
Edward C. Frackelton 1 ,
Andrew W. Eckert 1 ,
Kiran Annaiah 1 ,
Margaret L. Lawson 6 ,
F. George Otieno 1 ,
Erin Santa 1 ,
Julie L. Shaner 1 ,
Ryan M. Smith 1 ,
Robert Skraban 1 ,
Marcin Imielinski 1 ,
Rosetta M. Chiavacci 1 ,
Robert W. Grundmeier 7 8 ,
Charles A. Stanley 9 ,
Susan E. Kirsch 10 ,
Daryl Waggott 11 ,
Andrew D. Paterson 12 ,
Dimitri S. Monos 3 13 ,
the DCCT/EDIC Research Group ,
Constantin Polychronakos 4 and
Hakon Hakonarson 1 2 3
1 Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
2 Division of Human Genetics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
3 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
4 Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada
5 Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
6 Division of Endocrinology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
7 Pediatric Research Consortium, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
8 Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
9 Division of Endocrinology, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
10 Markham-Stouffville Hospital, Markham, Ontario, Canada
11 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Center for Health Research, Toronto, Ontario, Canada
12 Department of Public Health Sciences, Hospital for Sick Kids, University of Toronto, Toronto, Ontario
13 Department of Pathology and Laboratory Medicine, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania
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.
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Follow-Up Analysis of Genome-Wide Association Data Identifies Novel Loci for Type 1 Diabetes

10.2337/db08-1022