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  • 1
    Online Resource
    Online Resource
    Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol‐Response Behaviors in Model Organisms
    Wiley ; 2017
    In:  Alcoholism: Clinical and Experimental Research Vol. 41, No. 5 ( 2017-05), p. 911-928
    Details
    In: Alcoholism: Clinical and Experimental Research, Wiley, Vol. 41, No. 5 ( 2017-05), p. 911-928
    Abstract: 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 COL 6A3 and suggestive association in 2 previously implicated loci, KLF 12 and RYR 3 . None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC 339975 is significant in case:control meta‐analysis, but not in a population sample. Knockdown of a COL 6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling‐induced convulsions in mice. Loss of function of the KLF 12 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 RYR 3 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 LOC 339975 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 COL 6A3 , KLF 12 , RYR 3, and LOC 339975 . Despite nonreplication of COL 6A3 , KLF 12, and RYR 3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC 339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNA s are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.
    Type of Medium: Online Resource
    ISSN: 0145-6008 , 1530-0277
    URL: Issue
    URL: Article
    DOI: 10.1111/acer.2017.41.issue-5
    DOI: 10.1111/acer.13362
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2046886-6
    detail.hit.zdb_id: 3167872-5
    SSG: 15,3
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  • 2
    Online Resource
    Online Resource
    A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect in Caenorhabditis elegans
    Oxford University Press (OUP) ; 2015
    In:  Genetics Vol. 199, No. 1 ( 2015-01-01), p. 135-149
    Details
    In: Genetics, Oxford University Press (OUP), Vol. 199, No. 1 ( 2015-01-01), p. 135-149
    Abstract: Understanding the genes and mechanisms involved in acute alcohol responses has the potential to allow us to predict an individual’s predisposition to developing an alcohol use disorder. To better understand the molecular pathways involved in the activating effects of alcohol and the acute functional tolerance that can develop to such effects, we characterized a novel ethanol-induced hypercontraction response displayed by Caenorhabditis elegans. We compared body size of animals prior to and during ethanol treatment and showed that acute exposure to ethanol produced a concentration-dependent decrease in size followed by recovery to their untreated size by 40 min despite continuous treatment. An increase in cholinergic signaling, leading to muscle hypercontraction, is implicated in this effect because pretreatment with mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, blocked ethanol-induced hypercontraction, as did mutations causing defects in cholinergic signaling (cha-1 and unc-17). Analysis of mutations affecting specific subunits of nAChRs excluded a role for the ACR-2R, the ACR-16R, and the levamisole-sensitive AChR and indicated that this excitation effect is dependent on an uncharacterized nAChR that contains the UNC-63 α-subunit. We performed a forward genetic screen and identified eg200, a mutation that affects a conserved glycine in EAT-6, the α-subunit of the Na+/K+ ATPase. The eat-6(eg200) mutant fails to develop tolerance to ethanol-induced hypercontraction and remains contracted for at least 3 hr of continuous ethanol exposure. These data suggest that cholinergic signaling through a specific α-subunit-containing nAChR is involved in ethanol-induced excitation and that tolerance to this ethanol effect is modulated by Na+/K+ ATPase function.
    Type of Medium: Online Resource
    ISSN: 1943-2631
    URL: Article
    DOI: 10.1534/genetics.114.171884
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2015
    detail.hit.zdb_id: 1477228-0
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    An Assay for Measuring the Effects of Ethanol on the Locomotion Speed of 〈em〉Caenorhabditis elegans〈/em〉
    MyJove Corporation ; 2015
    In:  Journal of Visualized Experiments , No. 98 ( 2015-04-09)
    Details
    In: Journal of Visualized Experiments, MyJove Corporation, , No. 98 ( 2015-04-09)
    Type of Medium: Online Resource
    ISSN: 1940-087X
    URL: Article
    DOI: 10.3791/52681
    Language: English
    Publisher: MyJove Corporation
    Publication Date: 2015
    detail.hit.zdb_id: 2259946-0
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  • 4
    Online Resource
    Online Resource
    Natural allelic variation modifies acute ethanol response phenotypes in wild strains of C. elegans
    Wiley ; 2023
    In:  Alcohol: Clinical and Experimental Research Vol. 47, No. 8 ( 2023-08), p. 1505-1517
    Details
    In: Alcohol: Clinical and Experimental Research, Wiley, Vol. 47, No. 8 ( 2023-08), p. 1505-1517
    Abstract: Genetic variation contributes to the likelihood that an individual will develop an alcohol use disorder (AUD). Traditional laboratory studies in animal models have elucidated the molecular pharmacology of ethanol, but laboratory‐derived genetic manipulations rarely model the naturally occurring genetic variation observed in wild populations. Rather, these manipulations are biased toward identifying genes of central importance in the phenotypes. Because changes in such genes can confer selective disadvantages, they are not ideal candidates for carrying AUD risk alleles in humans. We sought to exploit Caenorhabditis elegans to identify allelic variation existing in the wild that modulates ethanol response behaviors. Methods We tested the acute ethanol responses of four strains recently isolated from the wild (JU1511, JU1926, JU1931, and JU1941) and 41 multiparental recombinant inbred lines (mpRILs) derived from them. We assessed locomotion at 10, 30, and 50 min on low and high ethanol concentrations. We performed principal component analyses (PCA) on the different phenotypes, tested for transgressive behavior, calculated heritability, and determined the correlations between behavioral responses. Results We observed a range of responses to ethanol across the strains. We detected a low‐concentration locomotor activation effect in some of the mpRILs not seen in the laboratory wild‐type strain. PCA showed different ethanol response behaviors to be independent. We observed transgressive behavior for many of the measured phenotypes and found that multiple behaviors were uncorrelated. The average broad‐sense heritability for all phenotypes was 23.2%. Conclusions Genetic variation significantly affects multiple acute ethanol response behaviors, many of which are independent of one another. This suggests that the genetic variation captured by these strains likely affects multiple biological mechanisms through which ethanol acts. Further study of these strains may allow these distinct mechanisms to be identified.
    Type of Medium: Online Resource
    ISSN: 2993-7175 , 2993-7175
    URL: Issue
    URL: Article
    DOI: 10.1111/acer.v47.8
    DOI: 10.1111/acer.15139
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 3167872-5
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  • 5
    Online Resource
    Online Resource
    An Assay for Measuring the Effects of Ethanol on the Locomotion Speed of 〈em〉Caenorhabditis elegans〈/em〉
    MyJove Corporation ; 2015
    In:  Journal of Visualized Experiments , No. 98 ( 2015-04-09)
    Details
    In: Journal of Visualized Experiments, MyJove Corporation, , No. 98 ( 2015-04-09)
    Type of Medium: Online Resource
    ISSN: 1940-087X
    URL: Article
    DOI: 10.3791/52681-v
    Language: English
    Publisher: MyJove Corporation
    Publication Date: 2015
    detail.hit.zdb_id: 2259946-0
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  • 6
    Online Resource
    Online Resource
    SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 10 ( 2015-03-10), p. 3032-3037
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 10 ( 2015-03-10), p. 3032-3037
    Abstract: Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans . We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1413451112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol
    Springer Science and Business Media LLC ; 2020
    In:  BMC Genomics Vol. 21, No. 1 ( 2020-12)
    Details
    In: BMC Genomics, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2020-12)
    Abstract: SWI/SNF chromatin remodeling genes are required for normal acute responses to alcohol in C. elegans and are associated with alcohol use disorder in two human populations. In an effort to discover the downstream genes that are mediating this effect, we identified SWI/SNF-regulated genes in C. elegans . Results To identify SWI/SNF-regulated genes in adults, we compared mRNA expression in wild type and swsn-1(os22ts) worms under conditions that produce inactive swsn-1 in mature cells. To identify SWI/SNF-regulated genes in neurons, we compared gene expression in swsn-9(ok1354) null mutant worms that harbor a neuronal rescue or a control construct . RNA sequencing was performed to an average depth of 25 million reads per sample using 50-base, paired-end reads. We found that 6813 transcripts were significantly differentially expressed between swsn-1(os22ts) mutants and wild-type worms and 2412 transcripts were significantly differentially expressed between swsn-9(ok1354) mutants and swsn-9(ok1354) mutants with neuronal rescue. We examined the intersection between these two datasets and identified 603 genes that were differentially expressed in the same direction in both comparisons; we defined these as SWI/SNF-regulated genes in neurons and in adults. Among the differentially expressed genes was cbp-1, a C. elegans homolog of the mammalian CBP/p300 family of histone acetyltransferases. CBP has been implicated in the epigenetic regulation in response to alcohol in animal models and a polymorphism in the human CBP gene, CREBBP, has been associated with alcohol-related phenotypes. We found that cbp-1 is required for the development of acute functional tolerance to alcohol in C. elegans . Conclusions We identified 603 transcripts that were regulated by two different SWI/SNF complex subunits in adults and in neurons. The SWI/SNF-regulated genes were highly enriched for genes involved in membrane rafts, suggesting an important role for this membrane microdomain in the acute alcohol response. Among the differentially expressed genes was cbp-1; CBP-1 homologs have been implicated in alcohol responses across phyla and we found that C. elegans cbp-1 was required for the acute alcohol response in worms.
    Type of Medium: Online Resource
    ISSN: 1471-2164
    URL: Article
    DOI: 10.1186/s12864-020-07059-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2041499-7
    SSG: 12
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