A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome

F. Bonfiglio, M. Henstrom, A. Nag, F. Hadizadeh, T. Zheng, M. C. Cenit, E. Tigchelaar, F. Williams, A. Reznichenko, W. E. Ek, N. V. Rivera, G. Homuth, A. A. Aghdassi, T. Kacprowski, M. Mannikko, V. Karhunen, L. Bujanda, J. Rafter, C. Wijmenga, J. RonkainenP. Hysi, A. Zhernakova, M. D'Amato*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

22 Citaten (Scopus)

Samenvatting

BackgroundIrritable 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.

MethodsBased 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 ResultsSuggestive GWAS signals (P5.0x10(-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=3.1x10(-10)) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk.

Conclusion & InferencesOur 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.

Originele taal-2English
Artikelnummer13358
Aantal pagina's11
TijdschriftNeurogastroenterology and motility
Volume30
Nummer van het tijdschrift9
DOI's
StatusPublished - sep-2018

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