A Human Type 1 Diabetes Susceptibility Locus Maps to Chromosome 21q22.3
Author:
Concannon Patrick12, Onengut-Gumuscu Suna23, Todd John A.4, Smyth Deborah J.4, Pociot Flemming5, Bergholdt Regine5, Akolkar Beena6, Erlich Henry A.7, Hilner Joan E.8, Julier Cécile9, Morahan Grant10, Nerup Jørn5, Nierras Concepcion R.11, Chen Wei-Min212, Rich Stephen S.2,
Affiliation:
1. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 2. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 3. Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia 4. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K 5. Steno Diabetes Center, Gentofte, Denmark 6. Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 7. Roche Molecular Systems, Pleasanton, California 8. Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina 9. INSERM U730 et CEA, Institut de Génomique Centre National de Génotypage, Evry, France 10. Centre for Diabetes Research, The Western Australian Institute for Medical Research, and Centre for Medical Research, University of Western Australia, Perth, Australia 11. Juvenile Diabetes Research Foundation, New York, New York 12. Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia
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.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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