Manuel Mattheisen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Dilafruz Juraeva, Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
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  • Jens Treutlein, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
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  • Henrike Scholz, Department of Animal Physiology, University of Cologne, Germany., Denmark
  • Josef Frank, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
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  • Franziska Degenhardt, 1] Institute of Human Genetics, University of Bonn, Germany [2] Department of Genomics, Life & Brain Center, University of Bonn, Germany.
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  • Sven Cichon, Department of Biomedicine, University Hospital Basel, Switzerland.
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  • Monika Ridinger, Department of Psychiatry, University of Regensburg, Germany.
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  • Manuel Mattheisen
  • Stephanie H Witt, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
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  • Maren Lang, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany., Denmark
  • Wolfgang H Sommer, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany., Denmark
  • Per Hoffmann, Department of Biomedicine, University Hospital Basel, Switzerland.
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  • Stefan Herms, Department of Biomedicine, University Hospital Basel, Switzerland.
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  • Norbert Wodarz, Department of Psychiatry, University of Regensburg, Germany.
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  • Michael Soyka, 1] Private Hospital Meiringen, Switzerland [2] Department of Psychiatry, University of Munich, Germany.
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  • Peter Zill, Department of Psychiatry, University of Munich, Germany.
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  • Wolfgang Maier, Department of Psychiatry, University of Bonn, Germany.
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  • Elisabeth Jünger, Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden., Denmark
  • Wolfgang Gaebel, Department of Psychiatry and Psychotherapy, University of Düsseldorf, Germany.
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  • Norbert Dahmen, Department of Psychiatry, University of Mainz, Germany.
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  • Norbert Scherbaum, Addiction Research Group at the Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Germany.
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  • Christine Schmäl, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
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  • Michael Steffens, Division of Research, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
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  • Susanne Lucae, Department of Psychiatric Pharmacogenetics, Max-Planck-Institute of Psychiatry, Germany.
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  • Marcus Ising, Department of Molecular Psychology, Max-Planck-Institute of Psychiatry, Germany.
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  • Michael N Smolka, Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden., Denmark
  • Ulrich S Zimmermann, Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden., Denmark
  • Bertram Müller-Myhsok, Department of Statistical Genetics, Max-Planck-Institute of Psychiatry, Germany.
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  • Markus M Nöthen, 1] Institute of Human Genetics, University of Bonn, Germany [2] Department of Genomics, Life & Brain Center, University of Bonn, Germany.
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  • Karl Mann, Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
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  • Falk Kiefer, Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
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  • Rainer Spanagel, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany., Denmark
  • Benedikt Brors, Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
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  • Marcella Rietschel, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.

Genetic factors play as large a role as environmental factors in the etiology of alcohol dependence. Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of alcohol dependence, many true findings may be missed due 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 five 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 alcohol dependence, presumably since more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in alcohol dependence 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.Neuropsychopharmacology accepted article preview online, 18 July 2014; doi:10.1038/npp.2014.178.

Original languageEnglish
JournalNeuropsychopharmacology
Volume40
Pages (from-to)361–371
ISSN0893-133X
DOIs
Publication statusPublished - 2015

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