Trynka, G and Hunt, KA and Bockett, NA and Romanos, J and Mistry, V and Szperl, A and Bakker, SF and Bardella, MT and Bhaw-Rosun, L and Castillejo, G and de la Concha, EG and de Almeida, RC and Dias, KR and van Diemen, CC and Dubois, PC and Duerr, RH and Edkins, S and Franke, L and Fransen, K and Gutierrez, J and Heap, GA and Hrdlickova, B and Hunt, S and Plaza Izurieta, L and Izzo, V and Joosten, LA and Langford, C and Mazzilli, MC and Mein, CA and Midah, V and Mitrovic, M and Mora, B and Morelli, M and Nutland, S and Núñez, C and Onengut-Gumuscu, S and Pearce, K and Platteel, M and Polanco, I and Potter, S and Ribes-Koninckx, C and Ricaño-Ponce, I and Rich, SS and Rybak, A and Santiago, JL and Senapati, S and Sood, A and Szajewska, H and Troncone, R and Varadé, J and Wallace, C and Wolters, VM and Zhernakova, A and Spanish Consortium on the Genetics of Coeliac Disease (CEGEC), and PreventCD Study Group, and Wellcome Trust Case Control Consortium (WTCCC), and Thelma, BK and Cukrowska, B and Urcelay, E and Bilbao, JR and Mearin, ML and Barisani, D and Barrett, JC and Plagnol, V and Deloukas, P and Wijmenga, C and van Heel, DA (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet , 43 (12) 1193 - 1201. 10.1038/ng.998.
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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.
|Title:||Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.|
|Additional information:||PMCID: PMC3242065|
|Keywords:||Case-Control Studies, Celiac Disease, Chromosome Mapping, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Haplotypes, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Risk Factors|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute|
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