Journal
PLOS GENETICS
Volume 7, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1001283
Keywords
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Categories
Funding
- Celiac Disease Consortium
- Innovative Cluster
- Dutch Government [BSIK03009]
- Netherlands Organization for Scientific Research (NWO) [918.66.620, 92.003.533, 907.00.281]
- Wellcome Trust [WT084743MA, 068545/Z/02, 085475]
- National Institutes of Allergy and Infectious Diseases [AI065687, AI067152]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK064869, DK062432]
- Crohn's and Colitis Foundation of America [SRA512]
- The Netherlands Organisation for Health Research and Development
- Royal Netherlands Academy of Arts and Sciences (KNAW)
- UK Medical Research Council [G0000934]
- MRC [G0000934, G1001158, G0700545] Funding Source: UKRI
- Medical Research Council [G0700545, G0000934] Funding Source: researchfish
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI065687, U19AI067152] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK043351, U01DK062432, R01DK064869] Funding Source: NIH RePORTER
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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 <1.0x10(-5) in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1x10(-2) in CelD and <1x10(-3) in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37x10(-8) and 6.39x10(-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 1.55x10(-10) and 1.38x10(-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.
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