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Neuropsychopharmacology. 2015 Jan;40(2):361-71. doi: 10.1038/npp.2014.178. Epub 2014 Jul 18.

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.

Author information

1
Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
2
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
3
Department of Animal Physiology, University of Cologne, Cologne, Germany.
4
1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
5
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
6
Department of Psychiatry, University of Regensburg, Regensburg, Germany.
7
Department of Biomedicine, University of Aarhus, Denmark.
8
Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
9
1] Private Hospital Meiringen, Meiringen, Switzerland [2] Department of Psychiatry, University of Munich, Munich, Germany.
10
Department of Psychiatry, University of Munich, Munich, Germany.
11
Department of Psychiatry, University of Bonn, Bonn, Germany.
12
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden.
13
Department of Psychiatry and Psychotherapy, University of Düsseldorf, Düsseldorf, Germany.
14
Department of Psychiatry, University of Mainz, Mainz, Germany.
15
Addiction Research Group at the Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany.
16
Division of Research, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
17
Department of Psychiatric Pharmacogenetics, Max-Planck-Institute of Psychiatry, München, Germany.
18
Department of Molecular Psychology, Max-Planck-Institute of Psychiatry, München, Germany.
19
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.
20
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

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.

PMID:
25035082
PMCID:
PMC4443948
DOI:
10.1038/npp.2014.178
[Indexed for MEDLINE]
Free PMC Article

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