Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms

Collaborative Study of the Genetics of Alcoholism Consortium, the German Study of the Genetics of Addiction Consortium

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)911-928
Number of pages18
JournalAlcoholism: Clinical and Experimental Research
Volume41
Issue number5
DOIs
StatePublished - May 1 2017

Fingerprint

Alcoholism
Ethanol
Genes
Alcohols
Long Noncoding RNA
Association reactions
Nucleus Accumbens
Alleles
Dantrolene
Brain
Gene Expression
Ryanodine Receptor Calcium Release Channel
Population Control
Caenorhabditis elegans
Brain Diseases
Ireland
Primates
Drosophila
Meta-Analysis
Motivation

Keywords

  • Alcohol Dependence
  • COL6A3
  • KLF12
  • LOC339975
  • RYR3

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Collaborative Study of the Genetics of Alcoholism Consortium, & the German Study of the Genetics of Addiction Consortium (2017). Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. Alcoholism: Clinical and Experimental Research, 41(5), 911-928. https://doi.org/10.1111/acer.13362

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. / Collaborative Study of the Genetics of Alcoholism Consortium; the German Study of the Genetics of Addiction Consortium.

In: Alcoholism: Clinical and Experimental Research, Vol. 41, No. 5, 01.05.2017, p. 911-928.

Research output: Contribution to journalArticle

Collaborative Study of the Genetics of Alcoholism Consortium & the German Study of the Genetics of Addiction Consortium 2017, 'Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms', Alcoholism: Clinical and Experimental Research, vol. 41, no. 5, pp. 911-928. https://doi.org/10.1111/acer.13362
Collaborative Study of the Genetics of Alcoholism Consortium, the German Study of the Genetics of Addiction Consortium. Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. Alcoholism: Clinical and Experimental Research. 2017 May 1;41(5):911-928. https://doi.org/10.1111/acer.13362
Collaborative Study of the Genetics of Alcoholism Consortium ; the German Study of the Genetics of Addiction Consortium. / Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. In: Alcoholism: Clinical and Experimental Research. 2017 ; Vol. 41, No. 5. pp. 911-928.
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T1 - Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms

AU - Collaborative Study of the Genetics of Alcoholism Consortium

AU - the German Study of the Genetics of Addiction Consortium

AU - Adkins, Amy E.

AU - Hack, Laura M.

AU - Bigdeli, Tim B.

AU - Williamson, Vernell S.

AU - McMichael, G. Omari

AU - Mamdani, Mohammed

AU - Edwards, Alexis C.

AU - Aliev, Fazil

AU - Chan, Robin F.

AU - Bhandari, Poonam

AU - Raabe, Richard C.

AU - Alaimo, Joseph T.

AU - Blackwell, Gina Mari G.

AU - Moscati, Arden

AU - Poland, Ryan S.

AU - Rood, Benjamin

AU - Patterson, Diana G.

AU - Walsh, Dermot

AU - Whitfield, John B.

AU - Zhu, Gu

AU - Montgomery, Grant W.

AU - Henders, Anjali K.

AU - Martin, Nicholas G.

AU - Heath, Andrew C.

AU - Madden, Pamela A.F.

AU - Frank, Josef

AU - Ridinger, Monika

AU - Wodarz, Norbert

AU - Soyka, Michael

AU - Zill, Peter

AU - Ising, Marcus

AU - Nöthen, Markus M.

AU - Kiefer, Falk

AU - Rietschel, Marcella

AU - Gelernter, Joel

AU - Sherva, Richard

AU - Koesterer, Ryan

AU - Almasy, Laura

AU - Zhao, Hongyu

AU - Kranzler, Henry R.

AU - Farrer, Lindsay A.

AU - Maher, Brion S.

AU - Prescott, Carol A.

AU - Dick, Danielle M.

AU - Bacanu, Silviu A.

AU - Edenberg, Howard

AU - Xuei, Xiaoling

AU - Nurnberger, John

AU - O'Connor, Sean

AU - Foroud, Tatiana

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - Alcohol Dependence

KW - COL6A3

KW - KLF12

KW - LOC339975

KW - RYR3

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