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

Gosia Trynka, Karen A. Hunt, Nicholas A. Bockett, Jihane Romanos, Vanisha Mistry, Agata Szperl, Sjoerd F. Bakker, Maria Teresa Bardella, Leena Bhaw-Rosun, Gemma Castillejo, Emilio G. De La Concha, Rodrigo Coutinho De Almeida, Kerith Rae M Dias, Cleo C. Van Diemen, Patrick C A Dubois, Richard H. Duerr, Sarah Edkins, Lude Franke, Karin Fransen, Javier GutierrezGraham A R Heap, Barbara Hrdlickova, Sarah Hunt, Leticia Plaza Izurieta, Valentina Izzo, Leo A B Joosten, Cordelia Langford, Maria Cristina Mazzilli, Charles A. Mein, Vandana Midah, Mitja Mitrovic, Barbara Mora, Marinita Morelli, Sarah Nutland, Concepción Núñez, Suna Onengut-Gumuscu, Kerra Pearce, Mathieu Platteel, Isabel Polanco, Simon Potter, Carmen Ribes-Koninckx, Isis Ricaño-Ponce, Stephen S. Rich, Anna Rybak, José Luis Santiago, Sabyasachi Senapati, Ajit Sood, Hania Szajewska, Riccardo Troncone, Jezabel Varadé, Chris Wallace, Victorien M. Wolters, Alexandra Zhernakova, B. K. Thelma, Bozena Cukrowska, Elena Urcelay, Jose Ramon Bilbao, M. Luisa Mearin, Donatella Barisani, Jeffrey C. Barrett, Vincent Plagnol, Panos Deloukas, Cisca Wijmenga, David A. Van Heel

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1193-1201
Number of pages9
JournalNature Genetics
Issue number12
Publication statusPublished - Dec 2011

ASJC Scopus subject areas

  • Genetics


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