title: XRCC5 as a risk gene for alcohol dependence: evidence from a genome-wide gene-set-based analysis and follow-up studies in Drosophila and humans.
abstract: Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence.
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Dilafruz
authors.initials: D
authors.lastname: Juraeva
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Treutlein
authors.affiliation: Department of Animal Physiology, University of Cologne, Cologne, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Scholz
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Department of Psychiatry, University of Regensburg, Regensburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Ridinger
authors.affiliation: Department of Biomedicine, University of Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Lang
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Sommer
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: Department of Psychiatry, University of Regensburg, Regensburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Wodarz
authors.affiliation: 1] Private Hospital Meiringen, Meiringen, Switzerland [2] Department of Psychiatry, University of Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Soyka
authors.affiliation: Department of Psychiatry, University of Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Zill
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jünger
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gaebel
authors.affiliation: Department of Psychiatry, University of Mainz, Mainz, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Dahmen
authors.affiliation: Addiction Research Group at the Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Scherbaum
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Schmäl
authors.affiliation: Division of Research, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.affiliation: Department of Psychiatric Pharmacogenetics, Max-Planck-Institute of Psychiatry, München, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.affiliation: Department of Molecular Psychology, Max-Planck-Institute of Psychiatry, München, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden.
authors.forename: Ulrich S
authors.initials: US
authors.lastname: Zimmermann
authors.affiliation: 1] Department of Statistical Genetics, Max-Planck-Institute of Psychiatry, München, Germany [2] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany [3] Institute of Translational Medicine Liverpool, University of Liverpool, Liverpool, UK.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Mann
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
mesh_terms: D000293:Adolescent; D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005858:Germany; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D044465:White People / Q000235:genetics
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen