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Alcohol Clin Exp Res. 2017 May;41(5):911-928. doi: 10.1111/acer.13362. Epub 2017 Mar 30.

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.

Author information

1
Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.
2
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
3
Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
4
Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
5
Shaftesbury Square Hospital, Belfast, United Kingdom.
6
Health Research Board, Dublin 2, Ireland.
7
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
8
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
9
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
10
Department of Psychiatry, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
11
Privatklinik Meiringen, Meiringen, Switzerland.
12
Department of Psychiatry and Psychotherapy, University of Munich, Munich, Germany.
13
Department of Molecular Psychology, Max-Planck-Institute of Psychiatry, Munich, Germany.
14
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
15
Institute of Human Genetics, University of Bonn, Bonn, Germany.
16
German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany.
17
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
18
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
19
Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut.
20
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
21
Department of Psychiatry, VA CT Healthcare Center, West Haven, Connecticut.
22
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.
23
Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
24
Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut.
25
Department of Psychiatry, Treatment Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
26
Philadelphia VA Medical Center, VISN 4 MIRECC, Philadelphia, Pennsylvania.
27
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.
28
Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts.
29
Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.
30
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
31
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
32
Department of Psychology, University of Southern California, Los Angeles, California.
33
Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
34
Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.

Abstract

BACKGROUND:

Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.

METHODS:

We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue.

RESULTS:

We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc).

CONCLUSIONS:

We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

KEYWORDS:

COL6A3 ; KLF12 ; LOC339975 ; RYR3 ; Alcohol Dependence

PMID:
28226201
PMCID:
PMC5404949
DOI:
10.1111/acer.13362
[Indexed for MEDLINE]
Free PMC Article

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