Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

J. C. Barrett, D. G. Clayton, P. Concannon, B. Akolkar, J. D. Cooper, H. A. Erlich, C. Julier, G. Morahan, J. Nerup, C. Nierras, V. Plagnol, F. Pociot, H. Schuilenburg, D. J. Smyth, H. Stevens, J. A. Todd, N. M. Walker, S. S. Rich, T. Baskerville, N. BautistaE. Bhatia, V. Bhatia, K. Bin Hasan, F. Bonnici, T. Brodnicki, F. Cameron, K. Chaichanwatanakul, P. T. Cheung, P. Colman, A. Cotterill, J. Couper, R. Cutfield, T. Davis, P. Dixon, K. Donaghue, K. Dowling, P. Drury, S. Dye, S. Gellert, R. Abdul Ghani, R. Greer, X. Han, L. Harrison, N. Homatopoulos, L. Ji, T. Jones, L. K. Yin, N. A. Kamaruddin, U. Kanga, A. Kanungo, G. Kaur, B. Kek, S. Knowles, J. Krebs, N. Kumar, Y. J. Lee, X. Li, S. Liktimaskul, M. Lloyd, A. Loth, A. Louey, N. Mehra, T. Merriman, L. Min, R. Moses, G. Mraz, R. Murphy, I. Nicholson, A. Panelo, P. Poh, G. Price, N. Ratnam, C. Sanjeevi, S. Sedimbi, S. Shen, G. S. Ying, B. Tait, N. Tandon, A. Thomas, M. Varney, P. Weerakulwattana, J. Willis, L. Albret, F. Ampudia-Blasco, J. Argente, G. Babadjanova, K. Badenhoop, T. Battelino, G. Beilhack, R. Bergholdt, P. Bingley, B. Boehm, J. Bolidson, C. Brorsson, J. Carlson, L. Castano, K. Chandler, O. Cinek, E. Cipponeri, R. Corripio, B. Garcia Cuartero, A. de Leiva, A. Fagulha, M. Fernandez Balcells, C. Guja, P. Gutierrez, E. Hatziagelaki, S. Heath, W. Helmberg, M. Hernandez, I. Holzheu, N. Hosszufalusi, C. Ionescu-Tirgoviste, J. Johannesen, C. Julier, H. Kahles, M. Knip, I. Kockum, E. Kojo, K. Koprivarova, O. Kordonouri, A. Kretowski, D. Krikovszky, A. Kurkhaus, N. Lalic, E. Lavant, A. Long, J. Ludvigsson, L. Madacsy, M. Marga, D. Mauricio, G. Mazurkievicz, J. Nerup, F. J. Novoa Mogollon, M. T. Petersen, M. Phillip, V. Pirags, F. Pociot, P. Pozzilli, R. Rappner, B. Roep, S. Rokni, S. Rosinger, O. Rubio-Cabezas, C. Ruckgaber, I. Satman, E. Schober, J. Seufert, R. Sing, J. Skrha, E. Sobngwi, M. Somerville, G. Spinas, V. Tillmann, D. Undlien, V. Urbanavicius, B. Van der Auwera, F. Vasquez San Miguel, A. Vazeo-Gerasimidi, D. Velickiene, A. Wagner, A. Williams, M. Wurzburger, A. Ziegler, M. Agleham, A. Aldrich, R. Alemzadeh, T. Aly, S. Arora, A. Austin, D. Becker, C. Benoist, N. Berka, S. Bhatia, P. Bonella, N. Bottini, S. Boyle, B. Brady, W. Brickman, R. Christensen, P. Concannon, R. Couch, D. Counts, J. Crandall, M. Daniels, L. Dolan, D. Donaldson, A. Doria, G. Eisenbarth, R. El-Hajj, H. Erlich, P. Fain, A. L. Fear, R. Ferry, R. Fiallo-Scharer, S. Ghosh, S. Gitelman, M. Godwin, R. Goland, N. Goodman, G. Goodwin, J. Gravely, C. Greenbaum, C. Gudgeon, F. Gunville, W. Hagopian, H. Hakonarson, J. Hansen, K. Harrington, J. Hassing, W. Hilliker, R. Hoffman, E. Hulbert, R. Izquierdo, N. Jospe, K. Kaiserman, F. Kaufman, S. Kim, E. Kloos, R. Kosoy, J. Lane, J. Lane, J. Lawrence, C. Levetan, P. Levin, R. Lipton, J. Lonsdale, V. Magnuson, J. Marks, B. Mayer-Davis, R. McEvoy, R. McIndoe, L. Merkle, D. Metzger, D. Miao, E. Mickelson, P. Moonsamy, W. Moore, A. Moran, J. Noble, G. Olsem, S. Onengut-Gumuscu, T. Orban, C. Orlowski, A. Paterson, M. Pietropaolo, C. Pihoker, C. Polychronakos, J. Post, D. Postellon, A. Pugliese, H. Qu, T. Quattrin, M. Rappaport, P. Raskin, H. Risbeck, H. Rodriguez, L. Rodriguez, M. Rogers, B. Russell, D. Schatz, C. Scott, J. X. She, D. Shulman, L. Soyka, P. Speiser, H. Starkman, A. Steck, S. Stender, L. Stratton, D. Sur, S. Taback, K. Thrailkill, E. Toth, P. Trymbiski, E. Tsalikian, K. Vertachnik, J. Wahlen, X. Wang, S. Weber, D. Wherrett, S. Willi, D. Wilson, J. Youkey, N. Young, L. Yu, D. Zimmerman, E. Adlem, J. Allen, J. Brown, O. Burren, P. Clarke, D. Clayton, G. Coleman, J. Cooper, Francesco Cucca, S. Duley, D. Dunger, V. Everett, M. Hardy, D. Harrison, I. Harrison, S. Hawkins, B. Healy, S. Hood, S. Howell, M. Maisuria, W. Meadows, T. Mistry, S. Nutland, N. Ovington, H. Schuilenburg, A. Simpson, L. Smink, H. Stevens, N. Taylor, J. Todd, J. Tuomilehto, N. Walker, B. Widmer, M. Wilson, H. Withers, M. Brown, W. M. Chen, A. Crews, J. Griffin, M. Hall, T. Harnish, J. Hepler, J. Hilner, N. King, K. Lohman, L. Lu, J. Mychaleckyj, J. Nail, L. Perdue, J. Pierce, D. Reboussin, S. Rich, S. Rushing, M. Sale, E. Sides, B. Snively, H. Teuschler, G. Theil, D. Williams, B. Akolkar, C. McKeon, C. Nierras, E. Thomson, D. Altshuler, K. Au, S. Bain, L. Barcellos, S. Barral, T. Becker, F. Briggs, P. Bronson, M. Daly, P. de Bakker, P. Deloukas, B. Devlin, M. C. Eike, L. Field, S. Gabriel, N. Garge, S. Gaudieri, B. Goldstein, C. Gorodezky, S. Hamon, C. He, J. Howson, K. Humphreys, I. James, M. Lathrop, B. A. Lie, D. Li, S. Mack, R. McGinnis, E. McKinnon, W. McLaren, D. Nolan, M. Olsson, J. Ott, D. Owerbach, C. Patterson, R. Podolsky, P. Ramsay, V. Rangantah, N. Risch, K. S. Ronningen, X. Shao, R. Single, M. Steffes, G. Thomson, A. M. Valdes, C. Vandiedonck, P. Whittaker, Q. Zhang

Research output: Contribution to journalArticlepeer-review

1137 Scopus citations

Abstract

Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P 10 6). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P 0.01; overall P 5 × 10 8) and 4 additional regions provided nominal evidence of replication (P 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.

Original languageEnglish (US)
Pages (from-to)703-707
Number of pages5
JournalNature Genetics
Volume41
Issue number6
DOIs
StatePublished - Jun 1 2009

Bibliographical note

Funding Information:
USA and UK multiplex families, respectively. Danish subjects were from the Danish Society of Childhood Diabetes (DSBD) and control DNA samples were provided by T. Hansen, O. Pedersen, K. Borch-Johnsen and T. Joergensen. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk.

Funding Information:
This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD) and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Further support was provided by a grant from the NIDDK (DK46635) to P.C. and a joint JDRF and Wellcome Trust grant to the Diabetes and Inflammation Laboratory at Cambridge, which also received support from the National Institute for Health Research Cambridge Biomedical Research Centre. D.C. is the recipient of a Wellcome Trust Principal Research Fellowship. We acknowledge the contributions of the following individuals: J. Alipaz, A. Simpson, J. Brown and J. Garsetti for assistance with project management; M. Hardy and K. Downes for genotyping; M. Maisuria for DNA sample coordination and quality control; J. Hilner and J. Pierce for managing T1DGC Data and DNA resources; J. Allen, N. Ovington, V. Everett, G. Dolman and M. Brown for data services and computing; and L. Smink, O. Burren, J. Mychaleckyj and N. Goodman for bioinformatics support.

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