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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. [ABSTRACT FROM AUTHOR]

Background Recurrent abdominal pain ( RAP) occurs frequently among children and is one of the cardinal symptoms of functional gastrointestinal disorders ( FGID). The mechanisms of visceral pain and RAP are not fully understood. A heritable component has been demonstrated and a few candidate genes proposed. NPSR1 encodes the receptor for neuropeptide S ( NPS) and NPS- NPSR1 signaling is involved in anxiety, inflammation, and nociception. NPSR1 polymorphisms are associated with asthma and chronic inflammatory diseases, but also with IBS-related intermediate phenotypes such as colonic transit time and rectal sensory ratings. Here, we sought to determine whether genetic variability in the NPSR1 gene influences the presence of RAP in children. Methods Twenty-eight single-nucleotide polymorphisms ( SNPs) in the NPSR1 gene region were successfully genotyped in 1744 children from the Swedish birth cohort BAMSE. Questionnaire information was used to define RAP as episodes of abdominal pain occurring at least once a month in 12-year-olds. Key Results The prevalence of RAP was 9% in BAMSE. Association with RAP was observed for seven NPSR1 SNPs, five of which withstood false discovery rate ( FDR) correction for multiple testing (best p = 0.00054, OR: 1.55 for SNP rs2530566). The associated SNPs all map in a putative regulatory region upstream NPSR1, where they may exert their genetic effects through the modulation of gene expression. Conclusions & Inferences Genetic variation at the NPSR1 locus impacts children's predisposition to RAP episodes in a Swedish population. [ABSTRACT FROM AUTHOR]