@article{c6a05ff919684f9f99f2223addc0cb16,
title = "Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms",
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 = "Alcohol Dependence, COL6A3, KLF12, LOC339975, RYR3",
author = "{Collaborative Study of the Genetics of Alcoholism Consortium} and {the German Study of the Genetics of Addiction Consortium} and Adkins, {Amy E.} and Hack, {Laura M.} and Bigdeli, {Tim B.} and Williamson, {Vernell S.} and McMichael, {G. Omari} and Mohammed Mamdani and Edwards, {Alexis C.} and Fazil Aliev and Chan, {Robin F.} and Poonam Bhandari and Raabe, {Richard C.} and Alaimo, {Joseph T.} and Blackwell, {Gina Mari G.} and Arden Moscati and Poland, {Ryan S.} and Benjamin Rood and Patterson, {Diana G.} and Dermot Walsh and Whitfield, {John B.} and Gu Zhu and Montgomery, {Grant W.} and Henders, {Anjali K.} and Martin, {Nicholas G.} and Heath, {Andrew C.} and Madden, {Pamela A.F.} and Josef Frank and Monika Ridinger and Norbert Wodarz and Michael Soyka and Peter Zill and Marcus Ising and N{\"o}then, {Markus M.} and Falk Kiefer and Marcella Rietschel and Joel Gelernter and Richard Sherva and Ryan Koesterer and Laura Almasy and Hongyu Zhao 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 Laura Bierut and John Rice and Kathleen Bucholz",
note = "Funding Information: BPR and KSK thank all the members of the Virginia Commonwealth University Alcohol Research Center for their invaluable insight and helpful discussions. AEA, TBB, LMH, FA, DMD, BSM, SAB, BTW, KSK, and BPR were supported by National Institute on Alcohol Abuse and Alcoholism grants P20 AA017828 to BPR, KSK, MFM, and DMD, R01 AA011408 to KSK and BPR, and R37 AA011408 to KSK. ACE was supported by National Institute on Alcohol Abuse and Alcoholism grant K01 AA021399. Sample collection was supported by previous funding of National Institute on Alcohol Abuse and Alcoholism grant R01 AA011408 to CAP and KSK. Control genotyping was supported by National Institute of Mental Health grant R01 MH083094 to BPR and Wellcome Trust Case Control Consortium 2 grant WTCCC-084710. MG thanks Lauren Thomas and Lara Lewellyn for expert technical assistance. Drosophila work was supported by National Institute on Alcohol Abuse and Alcoholism grants P20 AA017828 and R01 AA020634 to MG and MFM. JCB, AGD, LDM, RCR, and JTA were supported by National Institute on Alcohol Abuse and Alcoholism grants P20 AA017828 to AGD and JCB and R01 AA016837 to JCB. Some strains were provided by the Caenorhabditis Genetics Center (CGC), which is funded by the NIH Office of Research Infrastructure Programs grant P40 OD010440. MFM was supported by P20 AA017828 and R01 AA020634. VIV, MM, GOM, and VSW were supported by R21 AA022749. Collaborative Study of the Genetics of Alcoholism (COGA): Victor Hesselbrock, Lance Bauer, Grace Chan, Howard J. Edenberg, Xiaoling Xuei, John Nurnberger Jr, Sean O'Connor, Tatiana Foroud, Daniel L. Koller, Leah Wetherill, Samuel Kuperman, John Kramer, Bernice Porjesz, Sun J. Kang, Niklas Manz, Madhavi Rangaswamy, Laura Bierut, John Rice, Kathleen Bucholz, John W. Rohrbaugh, Jen C. Wang, Alison Goate, Marc Schuckit, Jay Tischfield, Andrew Brooks, Laura Almasy, Robert E. Taylor, Danielle M. Dick. German Study of the Genetics of Addictions (GESGA): Josef Frank, MSc, Sven Cichon, PhD, Jens Treutlein, PhD, Monika Ridinger, MD, Manuel Mattheisen, MD, Per Hoffmann, PhD, Stefan Herms, MSc, Norbert Wodarz, MD, Michael Soyka, MD, Peter Zill, PhD, Wolfgang Maier, MD, Rainald M{\"o}ssner, MD, Franziska Degenhardt, MD, Wolfgang Gaebel, MD, Norbert Dahmen, MD, Norbert Scherbaum, MD, Christine Schm{\"a}l, MD, Michael Steffens, MD, Susanne Lucae, MD, Marcus Ising, MD, Bertram M{\"u}ller-Myhsok, MD, Markus M. N{\"o}then, MD, Karl Mann, MD, Falk Kiefer, MD, and Marcella Rietschel, MD. Publisher Copyright: Copyright {\textcopyright} 2017 by the Research Society on Alcoholism",
year = "2017",
month = may,
doi = "10.1111/acer.13362",
language = "English",
volume = "41",
pages = "911--928",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
number = "5",
}