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.
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Adkins
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Hack
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Tim B
authors.initials: TB
authors.lastname: Bigdeli
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Vernell S
authors.initials: VS
authors.lastname: Williamson
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: G Omari
authors.initials: GO
authors.lastname: McMichael
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Mamdani
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Alexis C
authors.identifier: http://orcid.org/0000-0002-4006-9710
authors.initials: AC
authors.lastname: Edwards
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Fazil
authors.initials: F
authors.lastname: Aliev
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Robin F
authors.initials: RF
authors.lastname: Chan
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Poonam
authors.initials: P
authors.lastname: Bhandari
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Raabe
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Alaimo
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: GinaMari G
authors.initials: GG
authors.lastname: Blackwell
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Arden
authors.initials: A
authors.lastname: Moscati
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Poland
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rood
authors.affiliation: Shaftesbury Square Hospital, Belfast, United Kingdom.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Patterson
authors.affiliation: Health Research Board, Dublin 2, Ireland.
authors.forename: Dermot
authors.initials: D
authors.lastname: Walsh
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
authors.forename: Gu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Pamela A F
authors.initials: PAF
authors.lastname: Madden
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Psychiatry, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Ridinger
authors.affiliation: Department of Psychiatry, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Wodarz
authors.affiliation: Privatklinik Meiringen, Meiringen, Switzerland.|Department of Psychiatry and Psychotherapy, University of Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Soyka
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Zill
authors.affiliation: Department of Molecular Psychology, Max-Planck-Institute of Psychiatry, Munich, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut.|Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.|Department of Psychiatry, VA CT Healthcare Center, West Haven, Connecticut.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Sherva
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Ryan
authors.initials: R
authors.lastname: Koesterer
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.|Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, Treatment Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.|Philadelphia VA Medical Center, VISN 4 MIRECC, Philadelphia, Pennsylvania.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Psychiatry, VA CT Healthcare Center, West Haven, Connecticut.|Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.|Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.|Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts.|Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Brion S
authors.initials: BS
authors.lastname: Maher
authors.affiliation: Department of Psychology, University of Southern California, Los Angeles, California.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Prescott
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.|Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Silviu A
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Mathies
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Davies
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.|Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.|Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Vladimirov
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Mike
authors.initials: M
authors.lastname: Grotewiel
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.|Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Bowers
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Bettinger
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Webb
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.|Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.|Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.|Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.|Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Brien P
authors.identifier: http://orcid.org/0000-0002-2408-8268
authors.initials: BP
authors.lastname: Riley
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans; D016022:Case-Control Studies; D004330:Drosophila; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D056426:Genetic Loci / Q000187:drug effects / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008875:Middle Aged; D023421:Models, Animal; D051381:Rats
chemical_list: D000431:Ethanol
keywords: 
  COL6A3
  ; 
  KLF12
  ; 
  LOC339975
  ; 
  RYR3
  ; Alcohol Dependence