F Bonfiglio1,2, M Henström2, A Nag3, F Hadizadeh2, T Zheng2, M C Cenit4, E Tigchelaar4, F Williams3, A Reznichenko2, W E Ek2,5, N V Rivera2, G Homuth6, A A Aghdassi7, T Kacprowski6, M Männikkö8, V Karhunen8,9,10, L Bujanda1,11, J Rafter2, C Wijmenga4, J Ronkainen8,12, P Hysi13, A Zhernakova4, M D'Amato1,14,15,16. 1. Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, Spain. 2. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 3. Department of Twin Research & Genetic Epidemiology, King's College London, London, England. 4. Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands. 5. Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden. 6. Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. 7. Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. 8. Center for Life Course Health Research, University of Oulu, Oulu, Finland. 9. Oulu University Hospital, Oulu, Finland. 10. Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 11. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain. 12. Primary Health Care Center, Tornio, Finland. 13. Department of Ophthalmology, King's College London, St Thomas' Hospital Campus, London, UK. 14. Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. 15. BioCruces Health Research Institute, Bilbao, Spain. 16. IKERBASQUE, Basque Science Foundation, Bilbao, Spain.
Abstract
BACKGROUND: Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. METHODS: Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. KEY RESULTS: Suggestive GWAS signals (P ≤ 5.0 × 10-6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10-10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. CONCLUSION & INFERENCES: Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.
BACKGROUND:Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. METHODS: Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. KEY RESULTS: Suggestive GWAS signals (P ≤ 5.0 × 10-6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10-10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. CONCLUSION & INFERENCES: Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.
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