Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

被引：603

作者：

Trynka, Gosia ^{[2
,3
]}

Hunt, Karen A. ^{[1
]}

Bockett, Nicholas A. ^{[1
]}

Romanos, Jihane ^{[2
,3
]}

Mistry, Vanisha ^{[1
]}

Szperl, Agata ^{[2
,3
]}

Bakker, Sjoerd F. ^{[4
]}

Bardella, Maria Teresa ^{[5
,6
]}

Bhaw-Rosun, Leena ^{[7
]}

Castillejo, Gemma ^{[8
]}

de la Concha, Emilio G. ^{[9
]}

de Almeida, Rodrigo Coutinho ^{[2
,3
]}

Dias, Kerith-Rae M. ^{[7
]}

van Diemen, Cleo C. ^{[2
,3
]}

Dubois, Patrick C. A. ^{[1
]}

Duerr, Richard H. ^{[10
,11
]}

Edkins, Sarah ^{[12
]}

Franke, Lude ^{[2
,3
]}

Fransen, Karin ^{[3
,13
]}

Gutierrez, Javier ^{[2
,3
]}

Heap, Graham A. R. ^{[1
]}

Hrdlickova, Barbara ^{[2
,3
]}

Hunt, Sarah ^{[12
]}

Plaza Izurieta, Leticia ^{[14
]}

Izzo, Valentina ^{[15
]}

Joosten, Leo A. B. ^{[16
,17
]}

Langford, Cordelia ^{[12
]}

Mazzilli, Maria Cristina ^{[18
]}

Mein, Charles A. ^{[7
]}

Midah, Vandana ^{[19
]}

Mitrovic, Mitja ^{[2
,3
,20
]}

Mora, Barbara ^{[18
]}

Morelli, Marinita ^{[15
]}

Nutland, Sarah ^{[21
]}

Nunez, Concepcion ^{[9
]}

Onengut-Gumuscu, Suna ^{[22
]}

Pearce, Kerra ^{[23
]}

Platteel, Mathieu ^{[2
,3
]}

Polanco, Isabel ^{[24
]}

Potter, Simon ^{[12
]}

Ribes-Koninckx, Carmen ^{[25
]}

Ricano-Ponce, Isis ^{[2
,3
]}

Rich, Stephen S.

Rybak, Anna ^{[26
]}

Luis Santiago, Jose ^{[9
]}

Senapati, Sabyasachi ^{[27
]}

Sood, Ajit

Szajewska, Hania ^{[28
]}

Troncone, Riccardo ^{[29
]}

Varade, Jezabel ^{[9
]}

机构：

[1] Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London, England

[2] Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[3] Univ Groningen, Groningen, Netherlands

[4] Vrije Univ VU Med Ctr, Dept Gastroenterol, Amsterdam, Netherlands

[5] Osped Maggiore Policlin Mangiagalli & Regina Elen, Fdn Ist Ricovero & Cura Carattere Sci IRCCS, Milan, Italy

[6] Univ Milan, Dept Med Sci, Milan, Italy

[7] Barts & London Queen Marys Sch Med & Dent, Genome Ctr, John Vane Sci Ctr, London, England

[8] Univ Rovira & Virgili, Dept Paediat Gastroenterol, Hosp Univ St Joan de Reus, E-43201 Reus, Spain

[9] Hosp Clin S Carlos, Dept Immunol, IdISSC, Madrid, Spain

[10] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA

[11] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[12] Wellcome Trust Sanger Inst, Cambridge, England

[13] Univ Med Ctr Groningen, Dept Gastroenterol, Groningen, Netherlands

[14] Hosp Cruces, Immunogenet Res Lab, Baracaldo, Bizkaia, Spain

[15] Univ Naples Federico II, European Lab Food Induced Dis, Naples, Italy

[16] Radboud Univ Nijmegen, Dept Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[17] Radboud Univ Nijmegen, Nijmegen Inst Infect Inflammat & Immun N4i, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[18] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy

[19] Dayanand Med Coll & Hosp, Ludhiana, Punjab, India

[20] Univ Maribor, Fac Med, Ctr Human Mol Genet & Pharmacogen, SLO-2000 Maribor, Slovenia

[21] Univ Cambridge, Juvenile Diabet Res Fdn, Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge, England

[22] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[23] UCL, Univ Coll London Genom, Inst Child Hlth, London, England

[24] Hosp La Paz, Dept Pediat Gastroenterol, Madrid, Spain

[25] La Fe Univ Hosp, Dept Pediat Gastroenterol, Valencia, Spain

[26] Childrens Mem Hlth Inst, Dept Gastroenterol Hepatol & Immunol, Warsaw, Poland

[27] Univ Delhi, Dept Genet, New Delhi, India

[28] Med Univ Warsaw, Dept Pediat, Warsaw, Poland

[29] Univ Naples Federico II, Dept Pediat, Naples, Italy

[30] Univ Med Ctr Utrecht, Dept Paediat Gastroenterol, Utrecht, Netherlands

[31] Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands

[32] Childrens Mem Hlth Inst, Dept Pathol, Warsaw, Poland

[33] Leiden Univ, Dept Paediat, Med Ctr, Leiden, Netherlands

[34] Univ Milano Bicocca, Dept Expt Med, Fac Med, Monza, Italy

[35] UCL, Univ Coll London Genet Inst, London, England

来源：

NATURE GENETICS | 2011年 / 43卷 / 12期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; RISK VARIANTS; LARGE-SCALE; POPULATION; PHENOTYPE; GENE; REGION; LOCI;

D O I：

10.1038/ng.998

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.

引用

页码：1193 / U45

页数：10

共 40 条

[1] Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus [J].

Adrianto, Indra ;

Wen, Feng ;

Templeton, Amanda ;

Wiley, Graham ;

King, Jarrod B. ;

Lessard, Christopher J. ;

Bates, Jared S. ;

Hu, Yanqing ;

Kelly, Jennifer A. ;

Kaufman, Kenneth M. ;

Guthridge, Joel M. ;

Alarcon-Riquelme, Marta E. ;

Anaya, Juan-Manuel ;

Bae, Sang-Cheol ;

Bang, So-Young ;

Boackle, Susan A. ;

Brown, Elizabeth E. ;

Petri, Michelle A. ;

Gallant, Caroline ;

Ramsey-Goldman, Rosalind ;

Reveille, John D. ;

Vila, Luis M. ;

Criswell, Lindsey A. ;

Edberg, Jeffrey C. ;

Freedman, Barry I. ;

Gregersen, Peter K. ;

Gilkeson, Gary S. ;

Jacob, Chaim O. ;

James, Judith A. ;

Kamen, Diane L. ;

Kimberly, Robert P. ;

Martin, Javier ;

Merrill, Joan T. ;

Niewold, Timothy B. ;

Park, So-Yeon ;

Pons-Estel, Bernardo A. ;

Scofield, R. Hal ;

Stevens, Anne M. ;

Tsao, Betty P. ;

Vyse, Timothy J. ;

Langefeld, Carl D. ;

Harley, John B. ;

Moser, Kathy L. ;

Webb, Carol F. ;

Humphrey, Mary Beth ;

Montgomery, Courtney Gray ;

Gaffney, Patrick M. .

NATURE GENETICS, 2011, 43 (03) :253-U102

[2] Hundreds of variants clustered in genomic loci and biological pathways affect human height [J].

Allen, Hana Lango ;

Estrada, Karol ;

Lettre, Guillaume ;

Berndt, Sonja I. ;

Weedon, Michael N. ;

Rivadeneira, Fernando ;

Willer, Cristen J. ;

Jackson, Anne U. ;

Vedantam, Sailaja ;

Raychaudhuri, Soumya ;

Ferreira, Teresa ;

Wood, Andrew R. ;

Weyant, Robert J. ;

Segre, Ayellet V. ;

Speliotes, Elizabeth K. ;

Wheeler, Eleanor ;

Soranzo, Nicole ;

Park, Ju-Hyun ;

Yang, Jian ;

Gudbjartsson, Daniel ;

Heard-Costa, Nancy L. ;

Randall, Joshua C. ;

Qi, Lu ;

Smith, Albert Vernon ;

Maegi, Reedik ;

Pastinen, Tomi ;

Liang, Liming ;

Heid, Iris M. ;

Luan, Jian'an ;

Thorleifsson, Gudmar ;

Winkler, Thomas W. ;

Goddard, Michael E. ;

Lo, Ken Sin ;

Palmer, Cameron ;

Workalemahu, Tsegaselassie ;

Aulchenko, Yurii S. ;

Johansson, Asa ;

Zillikens, M. Carola ;

Feitosa, Mary F. ;

Esko, Tonu ;

Johnson, Toby ;

Ketkar, Shamika ;

Kraft, Peter ;

Mangino, Massimo ;

Prokopenko, Inga ;

Absher, Devin ;

Albrecht, Eva ;

Ernst, Florian ;

Glazer, Nicole L. ;

Hayward, Caroline .

NATURE, 2010, 467 (7317) :832-838

[3] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[4] A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat [J].

Asano, Atsushi ;

Tsubomatsu, Kouta ;

Jung, Cha-Gyun ;

Sasaki, Nobuya ;

Agui, Takashi .

MAMMALIAN GENOME, 2007, 18 (11) :779-786

[5] Rare Variant Association Analysis Methods for Complex Traits [J].

Asimit, Jennifer ;

Zeggini, Eleftheria .

ANNUAL REVIEW OF GENETICS, VOL 44, 2010, 44 :293-308

[6] Undiagnosed coeliac disease at age seven: population based prospective birth cohort study [J].

Bingley, PJ ;

Williams, AJK ;

Norcross, AJ ;

Unsworth, DJ ;

Lock, RJ ;

Ness, AR ;

Jones, RW .

BRITISH MEDICAL JOURNAL, 2004, 328 (7435) :322-323

[7] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[8] Population structure, differential bias and genomic control in a large-scale, case-control association study [J].

Clayton, DG ;

Walker, NM ;

Smyth, DJ ;

Pask, R ;

Cooper, JD ;

Maier, LM ;

Smink, LJ ;

Lam, AC ;

Ovington, NR ;

Stevens, HE ;

Nutland, S ;

Howson, JMM ;

Faham, M ;

Moorhead, M ;

Jones, HB ;

Falkowski, M ;

Hardenbol, P ;

Willis, TD ;

Todd, JA .

NATURE GENETICS, 2005, 37 (11) :1243-1246

[9] Promise and pitfalls of the Immunochip [J].

Cortes, Adrian ;

Brown, Matthew A. .

ARTHRITIS RESEARCH & THERAPY, 2011, 13 (01)

[10] Rare Variants Create Synthetic Genome-Wide Associations [J].

Dickson, Samuel P. ;

Wang, Kai ;

Krantz, Ian ;

Hakonarson, Hakon ;

Goldstein, David B. .

PLOS BIOLOGY, 2010, 8 (01)

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