Dual‐Trait Selection for Ethanol Consumption and Withdrawal: Genetic and Transcriptional Network Effects

Metten, Pamela; Iancu, Ovidiu D.; Spence, Stephanie E.; Walter, Nicole A.R.; Oberbeck, Denesa; Harrington, Christina A.; Colville, Alexandre; McWeeney, Shannon K.; Phillips, Tamara J.; Buck, Kari J.; Crabbe, John C.; Belknap, John K.; Hitzemann, Robert

doi:10.1111/acer.12574

Cited by 29 publications

(57 citation statements)

References 41 publications

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“…We used a bootstrapping procedure comparing average module connectivity to that of random gene groups to confirm network partition accuracy (Langfelder et al, 2011; Metten et al, 2014). This procedure generates Z scores for each module as a measure of quality: >2 is considered moderate and >10 is considered high.…”

Section: Resultsmentioning

confidence: 99%

“…Parallel WGCNA (Zhang and Horvath, 2005; Langfelder and Horvath, 2008) were performed similarly to previous work (Iancu et al, 2012; Metten et al, 2014) using the R8B6 and R2D2 datasets. Expression data were first filtered for detection across all samples.…”

Section: Methodsmentioning

confidence: 99%

“…Details of our approach (based upon Langfelder and Horvath, 2008; Langfelder et al, 2011) are provided in previous work (Metten et al, 2014). In these, module membership (kME) is a natural measure of connectivity that describes how closely a probe/gene resembles the ME, and intramodular connectivity (kWithin) is calculated as the sum of connection strengths within distinct modules (Langfelder and Horvath, 2008).…”

Section: Methodsmentioning

confidence: 99%

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A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal

et al. 2017

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Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified quantitative trait loci on distal mouse chromosome 1 with large effects on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice (Alcdp1 and Alcw1, respectively). We fine-mapped these loci to a 1.1–1.7 Mb interval syntenic with human 1q23.2-23.3. Alcw1/Alcdp1 interval genes show remarkable genetic variation among mice derived from the C57BL/6J and DBA/2J strains, the two most widely studied genetic animal models for alcohol-related traits. Here, we report the creation of a novel recombinant Alcw1/Alcdp1 congenic model (R2) in which the Alcw1/Alcdp1 interval from a donor C57BL/6J strain is introgressed onto a uniform, inbred DBA/2J genetic background. As expected, R2 mice demonstrate significantly less severe alcohol withdrawal compared to wild-type littermates. Additionally, comparing R2 and background strain animals, as well as reciprocal congenic (R8) and appropriate background strain animals, we assessed Alcw1/Alcdp1 dependent brain gene expression using microarray and quantitative PCR analyses. To our knowledge this includes the first Weighted Gene Co-expression Network Analysis using reciprocal congenic models. Importantly, this allows detection of co-expression patterns limited to one or common to both genetic backgrounds with high or low predisposition to alcohol withdrawal severity. The gene expression patterns (modules) in common contain genes related to oxidative phosphorylation, building upon human and animal model studies that implicate involvement of oxidative phosphorylation in alcohol use disorders (AUDs). Finally, we demonstrate that administration of N-acetylcysteine, an FDA-approved antioxidant, significantly reduces symptoms of alcohol withdrawal (convulsions) in mice, thus validating a phenotypic role for this network. Taken together, these studies support the importance of mitochondrial oxidative homeostasis in alcohol withdrawal and identify this network as a valuable therapeutic target in human AUDs.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal

et al. 2017

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“…Interestingly, several studies have implicated the Kcnq family of genes in preclinical rodent alcohol drinking models. Kcnq2 expression was increased in the ventral striatum of mice selectively bred for high alcohol consump tion/low withdrawal severity compared with those bred for low alcohol consumption/high withdrawal severity (Table 2) [84]. Additionally, these authors found that Kcnq2 was a positional candidate within the ciseQTL for alcohol consumption and withdrawal.…”

Section: Preclinical Pharamcogenetic Targets For Treating Alcohol Addmentioning

confidence: 92%

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

Rinker

Mulholland

2017

Pharmacogenomics

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Inherited genetic variants contribute to risk factors for developing an alcohol use disorder, and polymorphisms may inform precision medicine strategies for treating alcohol addiction. Targeting genetic mutations linked to alcohol phenotypes has provided promising initial evidence for reducing relapse rates in alcoholics. Although successful in some studies, there are conflicting findings and the reports of adverse effects may ultimately limit their clinical utility, suggesting that novel pharmacogenetic targets are necessary to advance precision medicine approaches. Here, we describe promising novel genetic variants derived from preclinical models of alcohol consumption and dependence that may uncover disease mechanisms that drive uncontrolled drinking and identify novel pharmacogenetic targets that facilitate therapeutic intervention for the treatment of alcohol use disorder. Alcohol use disorder (AUD) is a chronic neurological disorder characterized by an inability to regulate alcohol intake despite a host of serious and harmful health, soci etal and personal consequences [1]. The cur rent pharmacotherapies available for AUD treatment have been met with variable out comes that are modest at best and thus have not been widely embraced by the medical community. This gap in treatment options provides an opportunity to explore new avenues toward identifying novel pharmaco therapeutic targets. As with other addictive disorders, AUD is influenced, to a consid erable degree, by genetics, with heritability estimates upward of 60% [2,3]. Despite the comparatively large influence of genetics, the exact etiology of AUD is by no means simple or straightforward, which under scores the difficulty in effective treatment of this disorder. In this review, we provide an evaluation of our understanding of the genet ics of AUD in relation to current precision medicine approaches. Demonstrating the considerable heterogeneity that exists within the AUD population and understanding the contribution of genetic variation to treatment response provides a framework for promot ing a pharmacogenetic approach. Moreover, understanding the genetic variation among individuals with AUD in treatment response will provide valuable information that will allow for personalized treatment plans.A diagnosis of AUD is based strictly on a set of clinical diagnostic criteria, because as of yet, there are no reliable biomarkers to identify AUD or subpopulations that might be more or less responsive to certain medica tions. This means that, at best, we are treat ing AUD by trial and error on a, presumably, largely heterogeneous population. There are currently only three US FDA approved pharmaco therapies for treating AUD, nal trexone, acamprosate and disulfiram, all of

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“…For example, Snapc3 was identified as a candidate in volved in ethanol consumption and withdrawal in a recent QTL study using a recombinant panel of BxD mice. 29 Snapc3 encodes a component of the small nuclear RNA (snRNA) activating complex required for the transcription of both RNA polymerase II and III snRNA genes. 30 Interestingly, our list of 28 genes also contains Snapc1, which encodes another component of this com plex potentially highlighting snRNA as an important class of molecules in the regulation of reinforcement.…”

Section: J Psychiatry Neurosci 2016;41(3)mentioning

confidence: 99%

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

Stacey

Lourdusamy

Ruggeri³

et al. 2016

jpn

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Background:The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2 -/-mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Methods: Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2 -/-mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). Results: The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct "modules," or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (p empirical < 0.001). Limitations: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2 -/-mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Conclusion: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2 -/-mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.A translational systems biology approach in both animals and humans J Psychiatry Neurosci 2016;41(3)193

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Dual‐Trait Selection for Ethanol Consumption and Withdrawal: Genetic and Transcriptional Network Effects

Cited by 29 publications

References 41 publications

A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal

A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

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