Genome-Wide Scan for Linkage to Type 1 Diabetes in 2,496 Multiplex Families From the Type 1 Diabetes Genetics Consortium
- Patrick Concannon1,2,
- Wei-Min Chen2,3,
- Cécile Julier4,
- Grant Morahan5,
- Beena Akolkar6,
- Henry A. Erlich7,
- Joan E. Hilner8,
- Jørn Nerup9,
- Concepcion Nierras10,
- Flemming Pociot9,
- John A. Todd11,
- Stephen S. Rich2 and
- the Type 1 Diabetes Genetics Consortium
- 1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia;
- 2Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia;
- 3Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia;
- 4INSERM U730, Centre National de Génotypage, Evry, France;
- 5Centre for Diabetes Research, The Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Australia;
- 6Division of Diabetes, Endocrinology, and Metabolic Diseases, The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
- 7Roche Molecular Systems, Pleasanton, California;
- 8Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina;
- 9Steno Diabetes Center, Gentofte, Denmark;
- 10Juvenile Diabetes Research Foundation, New York, New York;
- 11Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
- Corresponding author: Patrick Concannon, patcon{at}virginia.edu.
Abstract
OBJECTIVE Type 1 diabetes arises from the actions of multiple genetic and environmental risk factors. Considerable success at identifying common genetic variants that contribute to type 1 diabetes risk has come from genetic association (primarily case-control) studies. However, such studies have limited power to detect genes containing multiple rare variants that contribute significantly to disease risk.
RESEARCH DESIGN AND METHODS The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled a collection of 2,496 multiplex type 1 diabetic families from nine geographical regions containing 2,658 affected sib-pairs (ASPs). We describe the results of a genome-wide scan for linkage to type 1 diabetes in the T1DGC family collection.
RESULTS Significant evidence of linkage to type 1 diabetes was confirmed at the HLA region on chromosome 6p21.3 (logarithm of odds [LOD] = 213.2). There was further evidence of linkage to type 1 diabetes on 6q that could not be accounted for by the major linkage signal at the HLA class II loci on chromosome 6p21. Suggestive evidence of linkage (LOD ≥2.2) was observed near CTLA4 on chromosome 2q32.3 (LOD = 3.28) and near INS (LOD = 3.16) on chromosome 11p15.5. Some evidence for linkage was also detected at two regions on chromosome 19 (LOD = 2.84 and 2.54).
CONCLUSIONS Five non–HLA chromosome regions showed some evidence of linkage to type 1 diabetes. A number of previously proposed type 1 diabetes susceptibility loci, based on smaller ASP numbers, showed limited or no evidence of linkage to disease. Low-frequency susceptibility variants or clusters of loci with common alleles could contribute to the linkage signals observed.
Footnotes
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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.
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- Received November 6, 2008.
- Accepted January 5, 2009.
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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.
- © 2009 by the American Diabetes Association.
