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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 Gastroesophageal reflux disease ( GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism ( SNP) genotypes. Methods We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis ( GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map ( cMap). Key results We identified 30 GERD suggestive risk loci (P≤5×10−5), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. Conclusions We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities. [ABSTRACT FROM AUTHOR]

To assess predictors of recurrence following laparoscopic radical hysterectomy (LRH) for apparent early stage cervical cancer (CC). This is a retrospective multi-institutional study reviewing data of consecutive patients who underwent LRH for FIGO 2009 stage IA1 (with lymphovascular space invasion (LVSI)), IA2 and IB1(≤4 cm) CC, between January 2006 and December 2017. The following histotypes were included: squamous, adenosquamous, and adenocarcinoma. Multivariable models were used to estimate adjusted odds ratio (OR) and corresponding 95% CI. Factors influencing disease-free survival (DFS) and disease-specific survival (DSS) were also explored. 428 patients were included in the analysis. With a median follow-up of 56 months (1–162) 54 patients recurred (12.6%). At multivariable analysis, tumor size (OR:1.04, 95%CI:1.01–1.09, p =.02), and presence of cervical residual tumor at final pathology (OR: 5.29, 95%CI:1.34–20.76, p =.02) were found as predictors of recurrence; conversely preoperative conization reduced the risk (OR:0.32, 95%CI:0.11–0.90, p =.03). These predictors remained significant also in the IB1 subgroup: tumor size: OR:1.05, 95%CI:1.01–1.09, p =.01; residual tumor at final pathology: OR: 6.26, 95%CI:1.58–24.83, p =.01; preoperative conization: OR:0.33, 95%CI:0.12–0.95, p =.04. Preoperative conization (HR: 0.29, 95%CI: 0.13–0.91; p =.03) and the presence of residual tumor on the cervix at the time of surgery (HR: 8.89; 95%CI: 1.39–17.23; p =.01) independently correlated with DFS. No independent factors were associated with DSS. In women with early stage CC the presence of high-volume disease at time of surgery represent an independent predictor of recurrence after LRH. Conversely, preoperative conization and the absence of residual disease at the time of surgery might play a protective role. • High-volume disease at time of surgery was an independent predictor of recurrence after laparoscopic radical hysterectomy. • Absence of residual tumor at final pathology had a protective role following laparoscopic surgery for early-stage disease. • Preoperative conization positively influenced disease-free survival in IA1(positive LVSI) – IB1cervical cancer. [ABSTRACT FROM AUTHOR]