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Nat Genet. 2015 Apr;47(4):381-6. doi: 10.1038/ng.3245. Epub 2015 Mar 9.

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.

Collaborators (426)

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

Author information

1
1] Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. [2] Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, USA.
2
1] Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. [2] Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
3
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
4
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
5
1] Department of Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
6
1] Department of Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Genetics, Stanford University, Stanford, California, USA. [4] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
7
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
8
Wellcome Trust Sanger Institute, Hinxton, UK.
9
1] Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. [2] Medical Research Council (MRC) Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge, UK.

Abstract

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.

PMID:
25751624
PMCID:
PMC4380767
DOI:
10.1038/ng.3245
[Indexed for MEDLINE]
Free PMC Article

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