Adkins, Amy E. and Hack, Laura M. and Bigdeli, Tim B. and Williamson, Vernell S. and McMichael, G. Omari and Mamdani, Mohammed and Edwards, Alexis C. and Aliev, Fazil and Chan, Robin F. and Bhandari, Poonam and Raabe, Richard C. and Alaimo, Joseph T. and Blackwell, GinaMari G. and Moscati, Arden and Poland, Ryan S. and Rood, Benjamin and Patterson, Diana G. and Walsh, Dermot and Whitfield, John B. and Zhu, Gu and Montgomery, Grant W. and Henders, Anjali K. and Martin, Nicholas G. and Heath, Andrew C. and Madden, Pamela A. F. and Frank, Josef and Ridinger, Monika and Wodarz, Norbert and Soyka, Michael and Zill, Peter and Ising, Marcus and Noethen, Markus M. and Kiefer, Falk and Rietschel, Marcella and Gelernter, Joel and Sherva, Richard and Koesterer, Ryan and Almasy, Laura and Zhao, Hongyu and Kranzler, Henry R. and Farrer, Lindsay A. and Maher, Brion S. and Prescott, Carol A. and Dick, Danielle M. and Bacanu, Silviu A. and Mathies, Laura D. and Davies, Andrew G. and Vladimirov, Vladimir I. and Grotewiel, Mike and Bowers, M. Scott and Bettinger, Jill C. and Webb, Bradley T. and Miles, Michael F. and Kendler, Kenneth S. and Riley, Brien P. (2017) Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 41 (5). pp. 911-928. ISSN 0145-6008, 1530-0277
Full text not available from this repository. (Request a copy)Abstract
BackgroundAlcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. MethodsWe 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. ResultsWe 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). ConclusionsWe 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RYANODINE RECEPTOR EXPRESSION; NATIONAL EPIDEMIOLOGIC SURVEY; TISSUE-PLASMINOGEN ACTIVATOR; DOPAMINE D-1 RECEPTORS; WIDE ASSOCIATION; CAENORHABDITIS-ELEGANS; PLACE PREFERENCE; NONCODING RNA; C. ELEGANS; WITHDRAWAL; Alcohol Dependence; COL6A3; KLF12; LOC339975; RYR3 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:10 |
| Last Modified: | 12 Feb 2019 14:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/975 |
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