University of Groningen A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease Festen,

Crohn’s disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value ,1.0610 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value ,1610 in CelD and ,1610 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37610 and 6.39610, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values ,0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55610 and 1.38610 respectively. Through a metaanalysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. Citation: Festen EAM, Goyette P, Green T, Boucher G, Beauchamp C, et al. (2011) A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn’s Disease and Celiac Disease. PLoS Genet 7(1): e1001283. doi:10.1371/journal.pgen.1001283 Editor: Michel Georges, University of Liège, Belgium Received March 10, 2010; Accepted December 20, 2010; Published January 27, 2011 Copyright: 2011 Festen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was supported by the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK03009); by the Netherlands Organization for Scientific Research (NWO, VICI grant 918.66.620 to CW, AGIKO grant 92.003.533 to EAMF, KF grant 907.00.281 to RKW); by the Wellcome Trust (grant WT084743MA to DAvH); by the National Institutes of Allergy and Infectious Diseases (grant AI065687, AI067152 to JDR); by the National Institute of Diabetes and Digestive and Kidney Diseases (grant DK064869, DK062432 to JDR); and by the Crohn’s and Colitis Foundation of America (grant SRA512 to JDR). EAMF is a MD-medical research trainee with financial support from The Netherlands Organisation for Health Research and Development. GT was awarded a Ter Meulen Fund travel grant by the Royal Netherlands Academy of Arts and Sciences (KNAW). PCD is a MRC Clinical Training Fellow (G0700545). The British 1958 Birth Cohort collection was funded by the UK Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02). Funding for the project Wellcome Trust Case-Control Consortium 2 data was provided by the Wellcome Trust under award 085475. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: R.K.Weersma@int.umcg.nl (RKW); john.david.rioux@umontreal.ca (JDR) . These authors contributed equally to this work. " These authors also contributed equally to this work. PLoS Genetics | www.plosgenetics.org 1 January 2011 | Volume 7 | Issue 1 | e1001283