Dense Genotyping Pinpoints Numerous Common and Rare Variant Association Signals in Celiac Disease
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Celiac.com 02/22/2012 - A research team recently conducted a dense genotyping non-HLA risk loci previously associated with immune-mediated diseases in individuals with celiac disease. The study was conducted under the auspices of the Genetics Department, University Medical Center and University of Groningen, The Netherlands.
The team used variants from the 1000 Genomes Project pilot European CEU dataset, along with data from additional re-sequencing studies, to densely genotype a total of 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease and in 12,228 control subjects.
They were able to discover thirteen new celiac disease risk loci reaching genome-wide significance. This discovery brings the number of loci known to be associated with celiac disease, including the HLA locus, to forty.
The team found multiple independent association signals in more than one in three of the loci. This is likely due to a combination of common, low-frequency and rare genetic variants.
Compared to earlier data, such as those from HapMap3, the large study group and the dense gene mapping made for a much higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions.
In all, the team found that 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements.
Finally, they defined the complex genetic architecture of the risk regions of celiac disease. They also refined the risk signals for celiac disease, which provide support for the next steps in understanding its causes.
The research team included G. Trynka, K. A. Hunt, N. A. Bockett, J. Romanos, V. Mistry, A. Szperl, S. F. Bakker, M. T. Bardella, L. Bhaw-Rosun, G. Castillejo, E. G. de la Concha, R. C. de Almeida, K. R. Dias, C. C. van Diemen, P.C. Dubois, R. H. Duerr, S. Edkins, L. Franke, K. Fransen, J. Gutierrez, G. A. Heap, B. Hrdlickova, S. Hunt, L. P. Izurieta, V. Izzo, L. A. Joosten, C. Langford, M. C. Mazzilli, C. A. Mein, V. Midah, M. Mitrovic, B. Mora, M. Morelli, S. Nutland, C. Núñez, S. Onengut-Gumuscu, K. Pearce, M. Platteel, I. Polanco, S. Potter, C. Ribes-Koninckx, I. Ricaño-Ponce, S. S. Rich, A. Rybak, J. L. Santiago, S. Senapati, A. Sood, H. Szajewska, R. Troncone, J. Varadé, C. Wallace, V. M. Wolters, and A. Zhernakova. The study team also included B. K. Thelma, B. Cukrowska, E. Urcelay, J. R. Bilbao, M. L. Mearin, D. Barisani, J. C. Barrett, V. Plagnol, P. Deloukas, C. Wijmenga, and D. A. van Heel, who are variously affiliated with the Spanish Consortium on the Genetics of Coeliac Disease (CEGEC), the PreventCD Study Group, and the Wellcome Trust Case Control Consortium (WTCCC).
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