Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
28226201
TITLE
Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-response Behaviors in Model Organisms.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
Alcohol Dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.
METHODS NlmCategory: METHODS
We conducted a genomewide association study in 706 related AD cases and 1748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms to assess the role of orthologous genes in ethanol response behaviors. We tested one primate-specific gene for expression differences in case/control post-mortem brain tissue.
RESULTS NlmCategory: RESULTS
We detected significant association in COL6A3 and suggestive association in two 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 C. elegans reduced ethanol 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. Klf12 expression correlated with locomotor activation following ethanol injection in mice. Loss of function of the RYR3 ortholog reduced ethanol sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer ethanol 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.
CONCLUSIONS NlmCategory: CONCLUSIONS
We detect association between AD and COL6A3, KLF12, RYR3 and LOC339975. Despite non-replication of COL6A3, KLF12 and RYR3 signals, orthologs of these genes influence behavioral response to ethanol in model organisms, suggesting potential involvement in human ethanol response and AD liability. The associated LOC339975 allele may influence gene expression in human nucleus accumbens. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
DATE PUBLISHED
2017 Feb 22
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2016/08/20
revised 2017/01/14
accepted 2017/02/16
entrez 2017/02/23 06:00
pubmed 2017/02/23 06:00
medline 2017/02/23 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Adkins AE Adkins Amy E AE Departments of Psychiatry.
Hack LM Hack Laura M LM Departments of Psychiatry.
Bigdeli TB Bigdeli Tim B TB Departments of Psychiatry.
Williamson VS Williamson Vernell S VS Departments of Psychiatry.
McMichael GO McMichael G Omari GO Departments of Psychiatry.
Mamdani M Mamdani Mohammed M Departments of Psychiatry.
Edwards A Edwards Alexis A Departments of Psychiatry.
Aliev F Aliev Fazil F Departments of Psychiatry.
Chan RF Chan Robin F RF Departments of Human & Molecular Genetics.
Bhandari P Bhandari Poonam P Departments of Human & Molecular Genetics.
Raabe RC Raabe Richard C RC Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Alaimo JT Alaimo Joseph T JT Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Blackwell GG Blackwell GinaMari G GG Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Moscati AA Moscati Arden A AA Departments of Psychiatry.
Poland RS Poland Ryan S RS Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Rood B Rood Benjamin B Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Patterson DG Patterson Diana G DG Shaftesbury Square Hospital, 116-120 Great Victoria Street, Belfast, BT2 7BG, United Kingdom.
Walsh D Walsh Dermot D Health Research Board, 67-72 Lower Mount Street, Dublin 2, Ireland.
Collaborative Study of the Genetics of Alcoholism Consortium
Whitfield JB Whitfield John B JB Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, 300 Herston Road, Brisbane, QLD 4006, Australia.
Zhu G Zhu Gu G Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, 300 Herston Road, Brisbane, QLD 4006, Australia.
Montgomery GW Montgomery Grant W GW Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, 300 Herston Road, Brisbane, QLD 4006, Australia.
Henders AK Henders Anjali K AK Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, 300 Herston Road, Brisbane, QLD 4006, Australia.
Martin NG Martin Nicholas G NG Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, 300 Herston Road, Brisbane, QLD 4006, Australia.
Heath AC Heath Andrew C AC Department of Psychiatry, Washington University School of Medicine, 4560 Clayton Ave., Suite 1000, St. Louis, MO, 63110, USA.
Madden PA Madden Pamela A F PA Department of Psychiatry, Washington University School of Medicine, 4560 Clayton Ave., Suite 1000, St. Louis, MO, 63110, USA.
Frank J Frank Josef J Departments of Genetic Epidemiology in Psychiatry.
Ridinger M Ridinger Monika M Department of Psychiatry, University Hospital Regensburg, University of Regensburg, 93042, Regensburg, Germany.
Wodarz N Wodarz Norbert N Department of Psychiatry, University Hospital Regensburg, University of Regensburg, 93042, Regensburg, Germany.
Soyka M Soyka Michael M Department of Psychiatry and Psychotherapy, University of Munich, Nussbaumstrasse 7, 80336, Munich, Germany.
Zill P Zill Peter P Department of Psychiatry and Psychotherapy, University of Munich, Nussbaumstrasse 7, 80336, Munich, Germany.
Ising M Ising Marcus M Department of Molecular Psychology, Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2-10, 80804, Munich, Germany.
Nöthen MM Nöthen Markus M MM German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Sigmund-Freud-Strasse 25, D-53127, Bonn, Germany.
Kiefer F Kiefer Falk F Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, J 5, 68159, Mannheim, Germany.
Rietschel M Rietschel Marcella M Departments of Genetic Epidemiology in Psychiatry.
German Study of the Genetics of Addiction Consortium
Gelernter J Gelernter Joel J Department of Psychiatry, VA CT Healthcare Center, 950 Campbell Avenue, West Haven, CT, 06516, USA.
Sherva R Sherva Richard R Departments of Medicine (Biomedical Genetics).
Koesterer R Koesterer Ryan R Departments of Medicine (Biomedical Genetics).
Almasy L Almasy Laura L Texas Biomedical Research Institute, Department of Genetics, P.O. Box 760549, San Antonio, TX, 78245-0549, USA.
Zhao H Zhao Hongyu H Biostatistics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.
Kranzler HR Kranzler Henry R HR VISN 4 MIRECC, Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, 19104, USA.
Farrer LA Farrer Lindsay A LA Department of Epidemiology and Biostatistics, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA.
Maher BS Maher Brion S BS Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 N. Broadway, 8th Floor, Baltimore, MD, 21205, USA.
Prescott CA Prescott Carol A CA Department of Psychology, University of Southern California, SGM 501, 3620 South McClintock Ave, Los Angeles, CA, 90089-1061, USA.
Dick DM Dick Danielle M DM Departments of Human & Molecular Genetics.
Bacanu SA Bacanu Silviu A SA Departments of Psychiatry.
Mathies LD Mathies Laura D LD Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Davies AG Davies Andrew G AG Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Vladimirov VI Vladimirov Vladimir I VI Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298-0533, PO Box 980533, USA.
Grotewiel M Grotewiel Mike M Departments of Human & Molecular Genetics.
Bowers MS Bowers M Scott MS Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Bettinger JC Bettinger Jill C JC Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Webb BT Webb Bradley T BT Departments of Psychiatry.
Miles MF Miles Michael F MF Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0424, PO Box 980424, USA.
Kendler KS Kendler Kenneth S KS Departments of Human & Molecular Genetics.
Riley BP Riley Brien P BP Departments of Human & Molecular Genetics.
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: Alcoholism, clinical and experimental research
ISOABBREVIATION: Alcohol. Clin. Exp. Res.
YEAR: 2017
MONTH: Feb
DAY: 22
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1530-0277
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Alcohol Clin Exp Res
COUNTRY: England
ISSNLINKING: 0145-6008
NLMUNIQUEID: 7707242
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
COL6A3
KLF12
LOC339975
RYR3
alcohol dependence
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
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