Journal article
Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms
Alcoholism, clinical and experimental research, Vol.41(5), pp.911-928
05/2017
DOI: 10.1111/acer.13362
PMCID: PMC5404949
PMID: 28226201
Abstract
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.
Details
- Title: Subtitle
- Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms
- Creators
- Amy E Adkins - Virginia Commonwealth UniversityLaura M Hack - Virginia Commonwealth UniversityTim B Bigdeli - Virginia Commonwealth UniversityVernell S Williamson - Virginia Commonwealth UniversityG Omari McMichael - Virginia Commonwealth UniversityMohammed Mamdani - Virginia Commonwealth UniversityAlexis C Edwards - Virginia Commonwealth UniversityFazil Aliev - Virginia Commonwealth UniversityRobin F Chan - Virginia Commonwealth UniversityPoonam Bhandari - Virginia Commonwealth UniversityRichard C Raabe - Virginia Commonwealth UniversityJoseph T Alaimo - Virginia Commonwealth UniversityGinaMari G Blackwell - Virginia Commonwealth UniversityArden Moscati - Virginia Commonwealth UniversityRyan S Poland - Virginia Commonwealth UniversityBenjamin Rood - Virginia Commonwealth UniversityDiana G Patterson - Shaftesbury Square Hospital, Belfast, United KingdomDermot Walsh - Health Research Board, Dublin 2, IrelandJohn B Whitfield - Royal Brisbane and Women's HospitalGu Zhu - Royal Brisbane and Women's HospitalGrant W Montgomery - Royal Brisbane and Women's HospitalAnjali K Henders - Royal Brisbane and Women's HospitalNicholas G Martin - Royal Brisbane and Women's HospitalAndrew C Heath - Washington University in St. LouisPamela A F Madden - Washington University in St. LouisJosef Frank - Heidelberg UniversityMonika Ridinger - University Hospital RegensburgNorbert Wodarz - University Hospital RegensburgMichael Soyka - Ludwig-Maximilians-Universität MünchenPeter Zill - Ludwig-Maximilians-Universität MünchenMarcus Ising - Max Planck SocietyMarkus M Nöthen - University of BonnFalk Kiefer - Heidelberg UniversityMarcella Rietschel - Heidelberg UniversityJoel Gelernter - Department of Psychiatry, VA CT Healthcare Center, West Haven, ConnecticutRichard Sherva - Boston UniversityRyan Koesterer - Boston UniversityLaura Almasy - Texas Biomedical Research InstituteHongyu Zhao - Yale UniversityHenry R Kranzler - University of PennsylvaniaLindsay A Farrer - Boston UniversityBrion S Maher - Johns Hopkins UniversityCarol A Prescott - University of Southern CaliforniaDanielle M Dick - Virginia Commonwealth UniversitySilviu A Bacanu - Virginia Commonwealth UniversityLaura D Mathies - Virginia Commonwealth UniversityAndrew G Davies - Virginia Commonwealth UniversityVladimir I Vladimirov - Virginia Commonwealth UniversityMike Grotewiel - Virginia Commonwealth UniversityM Scott Bowers - Virginia Commonwealth UniversityJill C Bettinger - Virginia Commonwealth UniversityBradley T Webb - Virginia Commonwealth UniversityMichael F Miles - Virginia Commonwealth UniversityKenneth S Kendler - Virginia Commonwealth UniversityBrien P Riley - Virginia Commonwealth UniversityCollaborative Study of the Genetics of Alcoholism ConsortiumGerman Study of the Genetics of Addiction Consortium
- Contributors
- Samuel Kuperman (Contributor) - University of Iowa, Psychiatry
- Resource Type
- Journal article
- Publication Details
- Alcoholism, clinical and experimental research, Vol.41(5), pp.911-928
- DOI
- 10.1111/acer.13362
- PMID
- 28226201
- PMCID
- PMC5404949
- NLM abbreviation
- Alcohol Clin Exp Res
- ISSN
- 0145-6008
- eISSN
- 1530-0277
- Publisher
- Wiley
- Grant note
- P20 AA017828 / NIAAA NIH HHS R37 AA011408 / NIAAA NIH HHS U01 AA016667 / NIAAA NIH HHS R01 MH083094 / NIMH NIH HHS R01 AA011408 / NIAAA NIH HHS K02 AA018755 / NIAAA NIH HHS R28 AA012725 / NIAAA NIH HHS K01 AA021399 / NIAAA NIH HHS P50 AA022537 / NIAAA NIH HHS
- Language
- English
- Date published
- 05/2017
- Academic Unit
- Psychiatry
- Record Identifier
- 9984293652302771
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