title: A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.
abstract: More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.
authors: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain mariona.bustamante@isglobal.org.|Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.|Pompeu Fabra University (UPF), Barcelona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
authors: Mariona
authors: M
authors: Bustamante
authors: Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors: Marie
authors: M
authors: Standl
authors: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.
authors: Quique
authors: Q
authors: Bassat
authors: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.|Pompeu Fabra University (UPF), Barcelona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
authors: Natalia
authors: N
authors: Vilor-Tejedor
authors: The Generation R Study Group, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Carolina
authors: C
authors: Medina-Gomez
authors: MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: Carolina
authors: C
authors: Bonilla
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Tarunveer S
authors: TS
authors: Ahluwalia
authors: Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Jonas
authors: J
authors: Bacelis
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Jonathan P
authors: JP
authors: Bradfield
authors: Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Ludwig-Maximilians-University of Munich, Dr. von Hauner Children's Hospital, Division of Metabolic Diseases and Nutritional Medicine, Munich, Germany.
authors: Carla M T
authors: CM
authors: Tiesler
authors: The Generation R Study Group, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Fernando
authors: F
authors: Rivadeneira
authors: MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: Susan
authors: S
authors: Ring
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Nadja H
authors: NH
authors: Vissing
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Nadia R
authors: NR
authors: Fink
authors: Department of Genetics and Bioinformatics, Area of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway.
authors: Astanand
authors: A
authors: Jugessur
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Frank D
authors: FD
authors: Mentch
authors: CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.|Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, València, Spain.
authors: Ferran
authors: F
authors: Ballester
authors: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors: Jennifer
authors: J
authors: Kriebel
authors: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands.|Leiden University College, The Hague, The Netherlands.
authors: Jessica C
authors: JC
authors: Kiefte-de Jong
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Helene M
authors: HM
authors: Wolsk
authors: CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.|Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, València, Spain.
authors: Sabrina
authors: S
authors: Llop
authors: Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Ludwig-Maximilians-University of Munich, Dr. von Hauner Children's Hospital, Division of Metabolic Diseases and Nutritional Medicine, Munich, Germany.
authors: Elisabeth
authors: E
authors: Thiering
authors: The Generation R Study Group, Erasmus MC, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands.
authors: Systke A
authors: SA
authors: Beth
authors: MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: Nicholas J
authors: NJ
authors: Timpson
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Josefine
authors: J
authors: Andersen
authors: Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors: Holger
authors: H
authors: Schulz
authors: The Generation R Study Group, Erasmus MC, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands.
authors: Vincent W V
authors: VW
authors: Jaddoe
authors: MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.|University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: David M
authors: DM
authors: Evans
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Johannes
authors: J
authors: Waage
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Hakon
authors: H
authors: Hakonarson
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Struan F A
authors: SF
authors: Grant
authors: Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Department of Genetics and Bioinformatics, Area of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway.
authors: Bo
authors: B
authors: Jacobsson
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Klaus
authors: K
authors: Bønnelykke
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Hans
authors: H
authors: Bisgaard
authors: MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: George
authors: G
authors: Davey Smith
authors: Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands.
authors: Henriette A
authors: HA
authors: Moll
authors: Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Inner City Clinic, University Hospital of Munich (LMU), Munich, Germany.
authors: Joachim
authors: J
authors: Heinrich
authors: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.|Pompeu Fabra University (UPF), Barcelona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.|IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.|Experimental Genetics, Sidra Medical and Research Centre, Doha, Qatar.
authors: Xavier
authors: X
authors: Estivill
authors: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.|Pompeu Fabra University (UPF), Barcelona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.|IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors: Jordi
authors: J
authors: Sunyer
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D003967:Diarrhea / Q000235:genetics* / Q000473:pathology; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D005647:Fucosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase