Amy E. Adkins, Virginia Commonwealth University
Laura M. Hack, Virginia Commonwealth University
Tim B. Bigdeli, Virginia Commonwealth University
Vernell S. Williamson, Virginia Commonwealth University
G. Omari McMichael, Virginia Commonwealth University
Mohammed Mamdani, Virginia Commonwealth University
Alexis C. Edwards, Virginia Commonwealth University
Fazil Aliev, Virginia Commonwealth University
Robin F. Chan, Virginia Commonwealth University
Poonam Bhandari, Virginia Commonwealth University
Richard C. Raabe, Virginia Commonwealth University
Joseph T. Alaimo, Virginia Commonwealth University
GinaMari G. Blackwell, Virginia Commonwealth University
Arden Moscati, Virginia Commonwealth University
Ryan S. Poland, Virginia Commonwealth University
Benjamin Rood, Virginia Commonwealth University
Diana G. Patterson, Shaftesbury Square Hospital
Dermot Walsh, Health Research Board
Collaborative Study of the Genetics of Alcoholism Consortium
John B. Whitfield, QIMR Berghofer Medical Research Institute
Gu Zhu, QIMR Berghofer Medical Research Institute
Grant W. Montgomery, QIMR Berghofer Medical Research Institute
Anjali K. Henders, QIMR Berghofer Medical Research Institute
Nicholas G. Martin, QIMR Berghofer Medical Research Institute
Andrew C. Heath, Washington University School of Medicine
Pamela A.F. Madden, Washington University School of Medicine
Josef Frank, Central Institute of Mental Health
Monika Ridinger, University Hospital Regensburg
Norbert Wodarz, University Hospital Regensburg
Michael Soyka, University of Munich
Peter Zill, University of Munich
Marcus Ising, Max-Planck-Institute of Psychiatry
Markus M. Nöthen, University of Bonn
Falk Kiefer, Central Institute of Mental Health
Marcella Rietschel, Central Institute of Mental Health
the German Study of the Genetics of Addiction Consortium
Joel Gelernter, Yale University School of Medicine
Richard Sherva, Boston University School of Medicine
Ryan Koesterer, Boston University School of Medicine
Laura Almasy, Texas Biomedical Research Institute
Hongyu Zhao, Yale University School of Medicine
Henry R. Kranzler, University of Pennsylvania Perelman School of Medicine
Lindsay A. Farrer, VA CT Healthcare Center
Brion S. Maher, Johns Hopkins Bloomberg School of Public Health
Carol A. Prescott, University of Southern California
Danielle M. Dick, Virginia Commonwealth University
Silviu A. Bacanu, Virginia Commonwealth University
Laura D. Mathies, Virginia Commonwealth University
Andrew G. Davies, Virginia Commonwealth University
Vladimir I. Vladimirov, Virginia Commonwealth University
Mike Grotewiel, Virginia Commonwealth University
M. Scott Bowers, Virginia Commonwealth University
Jill C. Bettinger, Virginia Commonwealth University
Bradley T. Webb, Virginia Commonwealth University
Michael F. Miles, Virginia Commonwealth University
Kenneth S. Kendler, Virginia Commonwealth University
Brien P. Riley, Virginia Commonwealth UniversityFollow

Document Type


Original Publication Date


Journal/Book/Conference Title






DOI of Original Publication



Originally published at

Date of Submission

June 2017



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


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.


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).


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.


Copyright © 2017 by the Research Society on Alcoholism.

Is Part Of

VCU Psychiatry Publications