Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 × 10−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and...

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Published inNature genetics Vol. 39; no. 7; pp. 857 - 864
Main Authors Todd, John A, Walker, Neil M, Cooper, Jason D, Smyth, Deborah J, Downes, Kate, Plagnol, Vincent, Bailey, Rebecca, Nejentsev, Sergey, Field, Sarah F, Payne, Felicity, Lowe, Christopher E, Szeszko, Jeffrey S, Hafler, Jason P, Zeitels, Lauren, Yang, Jennie H M, Vella, Adrian, Nutland, Sarah, Stevens, Helen E, Schuilenburg, Helen, Coleman, Gillian, Maisuria, Meeta, Meadows, William, Smink, Luc J, Healy, Barry, Burren, Oliver S, Lam, Alex A C, Ovington, Nigel R, Allen, James, Adlem, Ellen, Leung, Hin-Tak, Wallace, Chris, Howson, Joanna M M, Guja, Cristian, Ionescu-Tîrgovi te, Constantin, Simmonds, Matthew J, Heward, Joanne M, Gough, Stephen C L, Dunger, David B, Wicker, Linda S, Clayton, David G
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 01.07.2007
Subjects
Adolescent
Autoimmune diseases
Biological and medical sciences
Case-Control Studies
Chromosome Mapping
Chromosomes
Diabetes
Diabetes Mellitus, Type 1 - genetics
Diabetes. Impaired glucose tolerance
Diagnosis
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Fundamental and applied biological sciences. Psychology
Genetic aspects
Genetic Predisposition to Disease
Genetics of eukaryotes. Biological and molecular evolution
Genome, Human
Genomics
Humans
Identification and classification
Medical sciences
Physiological aspects
Polymorphism, Single Nucleotide
Quantitative trait loci
Single nucleotide polymorphisms
Thyroid diseases
Type 1 diabetes
United Kingdom
Endocrinopathy
Immunopathology
Association
Type 1 diabetes
Autoimmune disease
Chromosome
Genome
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Summary:The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 × 10−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (Pfollow-up ≤ 1.35 × 10−9; Poverall ≤ 1.15 × 10−14), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (Poverall = 1.38 × 10−8) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten.
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Current address: Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, 55905, USA.
These authors contributed equally to this work.
AUTHOR CONTRIBUTIONS
J.A.T. participated in the conception, design and coordination of the study; data analysis and drafting of the manuscript. N.M.W. managed the data and helped coordinate the study. J.D.C. analyzed data and drafted the manuscript. D.J.S. genotyped the nsSNP study and contributed to follow-up genotyping of the nsSNP and WTCCC studies, sequencing and genotyping of IL2 and SOCS1, data analysis and drafting of the manuscript. K.D. contributed to follow-up genotyping of the nsSNP and WTCCC studies, sequencing and genotyping of PTPN2 and data analysis. V.P. developed the nsSNP scoring algorithm and contributed to data analysis. R.B. genotyped the nsSNP study and contributed to follow-up genotyping of the nsSNP study. S.N. sequenced KIAA0350 and contributed to its bioinformatics analysis, participated in the follow-up genotyping of the WTCCC study and genotyped and analyzed 12q24 SNPs. S.F.F. genotyped the nsSNP study and contributed to follow-up genotyping of the nsSNP study. F.P. sequenced and genotyped CIITA. C.E.L. sequenced and genotyped IL21. J.S.S. genotyped and analyzed the gvSNPs. J.P.H. genotyped CD226 SNPs. L.Z. contributed to follow-up genotyping of the WTCCC scan and bioinformatics analysis. J.Y. contributed to follow-up genotyping of the WTCCC study. A.V. genotyped the IL2RB tag SNPs. S. Nutland, H.E.S., H.S., G.C., M.M. and W.M. were responsible for the DNA. L.J.S., B.H., O.S.B. and A.L. provided bioinformatics support. N.R.O. managed subject exclusions and SNP exclusions and the database for the nsSNP study. J.A. and E.A. provided T1DBase support. H.L. and C.W. produced Supplementary Figure 1 and provided statistical support. J.M.M.H. performed statistical analysis; C.G. and C.T. collected the Romanian families; Jaakko Tuomilehto, Leena Kinnunen, Eva Tuomilehto-Wolf, Valma Harjutsalo and Timo Valle of GET1FIN collected the Finnish families; M.J.S., J.M.H. and S.C.L.G. provided the Graves' disease cases and genotyping of rs1990760; WTCCC carried out the 500,000-SNP GWA study; D.B.D collected the T1D cases; L.S.W. discovered the CD226 nsSNP splice sequence alterations and contributed to the overall planning of the study and D.G.C. participated in the conception, design and coordination of the study; data analysis and drafting of the manuscript.
ISSN:1061-4036
1546-1718
DOI:10.1038/ng2068