title: 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.
abstract: 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 <1.0 x 10⁻⁵ in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value < 1 x 10⁻² in CelD and < 1 x 10⁻³ in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37 x 10⁻⁸ and 6.39 x 10⁻⁹, 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 1.55 x 10⁻¹⁰ and 1.38 x 10⁻¹¹ respectively. Through a meta-analysis 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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Eleonora A M
authors.initials: EA
authors.lastname: Festen
authors.forename: Philippe
authors.initials: P
authors.lastname: Goyette
authors.forename: Todd
authors.initials: T
authors.lastname: Green
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Boucher
authors.forename: Claudine
authors.initials: C
authors.lastname: Beauchamp
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Dubois
authors.forename: Caroline
authors.initials: C
authors.lastname: Lagacé
authors.forename: Pieter C F
authors.initials: PC
authors.lastname: Stokkers
authors.forename: Daan W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Donatella
authors.initials: D
authors.lastname: Barisani
authors.forename: Orazio
authors.initials: O
authors.lastname: Palmieri
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
mesh_terms: D002446:Celiac Disease / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D003627:Data Interpretation, Statistical; D020690:GTPase-Activating Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics*; D012307:Risk Factors
chemical_list: D020690:GTPase-Activating Proteins; C115629:IL18RAP protein, human; D053728:Interleukin-18 Receptor beta Subunit; C557017:TAGAP protein, human; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D006836:Hydro-Lyases; C022479:pseudouridylate synthetase