title: A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population.
abstract: 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).
  
  
  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.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Bonfiglio
authors.affiliation: Department of Ophthalmology, King's College London, St Thomas' Hospital Campus, London, UK.
authors.forename: P G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: W
authors.initials: W
authors.lastname: Ek
authors.affiliation: Center for Life Course Health Research, University of Oulu, Oulu, Finland.|Oulu University Hospital, Oulu, Finland.
authors.forename: V
authors.initials: V
authors.lastname: Karhunen
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: N V
authors.initials: NV
authors.lastname: Rivera
authors.affiliation: Center for Life Course Health Research, University of Oulu, Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Männikkö
authors.affiliation: Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Nordenstedt
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Zucchelli
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Bresso
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Williams
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Tornblom
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P K
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: N L
authors.initials: NL
authors.lastname: Pedersen
authors.affiliation: Primary Health Care Centre, Tornio, Finland.|Center for Family Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Ronkainen
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: P T
authors.initials: PT
authors.lastname: Schmidt
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|BioCruces Health Research Institute and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
authors.forename: M
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D005387:Finland / Q000453:epidemiology; D005764:Gastroesophageal Reflux / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D011159:Population Surveillance / Q000379:methods*; D013548:Sweden / Q000453:epidemiology; D018433:Twin Studies as Topic / Q000379:methods; D006113:United Kingdom / Q000453:epidemiology
keywords: GERD; SNP; genetics; genome-wide association studies; meta-analysis; risk loci