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

Trynka, Gosia, Hunt, Karen A, Bockett, Nicholas A, Romanos, Jihane, Mistry, Vanisha, Szperl, Agata, Bakker, Sjoerd F, Bardella, Maria Teresa, Bhaw-Rosun, Leena, Castillejo, Gemma, de la Concha, Emilio G, de Almeida, Rodrigo Coutinho, Dias, Kerith-Rae M, van Diemen, Cleo C, Dubois, Patrick C A, Duerr, Richard H, Edkins, Sarah, Franke, Lude, Fransen, Karin, Gutierrez, Javier, Heap, Graham A R, Hrdlickova, Barbara, Hunt, Sarah, Izurieta, Leticia Plaza, Izzo, Valentina, Joosten, Leo A B, Langford, Cordelia, Mazzilli, Maria Cristina, Mein, Charles A, Midah, Vandana, Mitrovic, Mitja, Mora, Barbara, Morelli, Marinita, Nutland, Sarah, Núñez, Concepción, Onengut-Gumuscu, Suna, Pearce, Kerra, Platteel, Mathieu, Polanco, Isabel, Potter, Simon, Ribes-Koninckx, Carmen, Ricaño-Ponce, Isis, Rich, Stephen S, Rybak, Anna, Santiago, José Luis, Senapati, Sabyasachi, Sood, Ajit, Szajewska, Hania, Troncone, Riccardo, Varadé, Jezabel, Wallace, Chris, Wolters, Victorien M, Zhernakova, Alexandra, Thelma, B K, Cukrowska, Bozena, Urcelay, Elena, Bilbao, Jose Ramon, Mearin, M Luisa, Barisani, Donatella, Barrett, Jeffrey C, Plagnol, Vincent, Deloukas, Panos, Wijmenga, Cisca, van Heel, David A and Craddock, Nicholas John ORCID: https://orcid.org/0000-0003-2171-0610 2011. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nature Genetics 43 (12) , pp. 1193-1201. 10.1038/ng.998

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	R Medicine > R Medicine (General)
Additional Information:	Nick Craddock is a member of the Wellcome Trust Case Control Consortium (WTCCC)
Publisher:	Macmillan Publishers Limited
ISSN:	1061-4036
Last Modified:	31 Oct 2022 09:07
URI:	https://orca.cardiff.ac.uk/id/eprint/79916

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