|
PMID |
|
|
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 |
|
|
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 |
|
|
|