scholarly journals Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

2018 ◽  
Author(s):  
Manav Kapoor ◽  
Jen-Chyong Wang ◽  
Sean P. Farris ◽  
Yunlong Liu ◽  
Jeanette McClintick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Alcohol Exposure ◽  
Biological Pathways ◽  
Genetic Associations ◽  
Altered Expression ◽  
Psychiatric Genetic ◽  
Coexpression Module ◽  
The Uk

ABSTRACTAlcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank’s alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

scholarly journals Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

2021 ◽  
Vol 11 (9) ◽  
pp. 1149
Author(s):  
Brent R. Kisby ◽  
Sean P. Farris ◽  
Michelle M. McManus ◽  
Florence P. Varodayan ◽  
Marisa Roberto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Alcohol Dependence ◽  
Functional Groups ◽  
Molecular Mechanisms ◽  
Alcohol Exposure ◽  
Cell Types ◽  
Behavioral Changes ◽  
Molecular Pathways ◽  
Chronic Alcohol

Alcohol dependence is associated with adverse consequences of alcohol (ethanol) use and is evident in most severe cases of alcohol use disorder (AUD). The central nucleus of the amygdala (CeA) plays a critical role in the development of alcohol dependence and escalation of alcohol consumption in dependent subjects. Molecular mechanisms underlying the CeA-driven behavioral changes are not well understood. Here, we examined the effects of alcohol on global gene expression in the CeA using a chronic intermittent ethanol (CIE) vapor model in rats and RNA sequencing (RNA-Seq). The CIE procedure resulted in robust changes in CeA gene expression during intoxication, as the number of differentially expressed genes (DEGs) was significantly greater than those expected by chance. Over-representation analysis of cell types, functional groups and molecular pathways revealed biological categories potentially important for the development of alcohol dependence in our model. Genes specific for astrocytes, myelinating oligodendrocytes, and endothelial cells were over-represented in the DEG category, suggesting that these cell types were particularly affected by the CIE procedure. The majority of the over-represented functional groups and molecular pathways were directly related to the functions of glial and endothelial cells, including extracellular matrix (ECM) organization, myelination, and the regulation of innate immune response. A coordinated regulation of several ECM metalloproteinases (e.g., Mmp2; Mmp14), their substrates (e.g., multiple collagen genes and myelin basic protein; Mbp), and a metalloproteinase inhibitor, Reck, suggests a specific mechanism for ECM re-organization in response to chronic alcohol, which may modulate neuronal activity and result in behavioral changes, such as an escalation of alcohol drinking. Our results highlight the importance of glial and endothelial cells in the effects of chronic alcohol exposure on the CeA, and demonstrate further insight into the molecular mechanisms of alcohol dependence in rats. These molecular targets may be used in future studies to develop therapeutics to treat AUD.

scholarly journals The potential impact of increased treatment rates for alcohol dependence in the United Kingdom in 2004

2021 ◽  
Author(s):  
Kevin D. Shield ◽  
Jürgen Rehm ◽  
Maximilien X. Rehm ◽  
Gerrit Gmel ◽  
Colin Drummond
Keyword(s):  
United Kingdom ◽  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Burden Of Disease ◽  
Pharmacological Treatment ◽  
Clinical Excellence ◽  
Sensitivity Analyses ◽  
Treatment Coverage ◽  
The United Kingdom ◽  
The Uk

Alcohol consumption has been linked to a considerable burden of disease in the United Kingdom (UK), with most of this burden due to heavy drinking and Alcohol Dependence (AD). However, AD is undertreated in the UK, with only 8% of those individuals with AD being treated in England and only 6% of those individuals with AD being treated in Scotland. Thus, the objective of this paper is to quantify the deaths that would have been avoided in the UK in 2004 if the treatment rate for AD had been increased. Methods Data on the prevalence of AD, alcohol consumption, and mortality were obtained from the Adult Psychiatric Morbidity Survey, the Global Information System on Alcohol and Health, and the 2004 Global Burden of Disease study respectively. Data on the effectiveness of pharmacological treatment and Motivational Interviewing/Cognitive Behavioural Therapy were obtained from Cochrane reviews and meta-analyses. Simulations were used to model the number of deaths under different treatment scenarios. Sensitivity analyses were performed to model the effects of Brief Interventions and to examine the effect of using AD prevalence data obtained from the National Institute for Health and Clinical Excellence. Results In the UK, 320 female and 1,385 male deaths would have been avoided if treatment coverage of pharmacological treatment had been increased to 20%. This decrease in the number of deaths represents 7.9% of all alcohol-attributable deaths (7.0% of all alcohol-attributable deaths for women and 8.1% of all alcohol-attributable deaths for men). If we used lower AD prevalence rates obtained from the National Institute for Health and Clinical Excellence, then treatment coverage of pharmacological treatment in hospitals for 20% of the population with AD would have resulted in the avoidance of 529 deaths in 2004 (99 deaths avoided for women and 430 deaths avoided for men). Conclusions Increasing AD treatment in the UK would have led to a large number of deaths being avoided in 2004. Increased AD treatment rates not only impact mortality but also impact upon the large burden of disability and morbidity attributable to AD, as well as the associated social and economic burdens.

scholarly journals The potential impact of increased treatment rates for alcohol dependence in the United Kingdom in 2004

2021 ◽  
Author(s):  
Kevin D. Shield ◽  
Jürgen Rehm ◽  
Maximilien X. Rehm ◽  
Gerrit Gmel ◽  
Colin Drummond
Keyword(s):  
United Kingdom ◽  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Burden Of Disease ◽  
Pharmacological Treatment ◽  
Clinical Excellence ◽  
Sensitivity Analyses ◽  
Treatment Coverage ◽  
The United Kingdom ◽  
The Uk

Alcohol consumption has been linked to a considerable burden of disease in the United Kingdom (UK), with most of this burden due to heavy drinking and Alcohol Dependence (AD). However, AD is undertreated in the UK, with only 8% of those individuals with AD being treated in England and only 6% of those individuals with AD being treated in Scotland. Thus, the objective of this paper is to quantify the deaths that would have been avoided in the UK in 2004 if the treatment rate for AD had been increased. Methods Data on the prevalence of AD, alcohol consumption, and mortality were obtained from the Adult Psychiatric Morbidity Survey, the Global Information System on Alcohol and Health, and the 2004 Global Burden of Disease study respectively. Data on the effectiveness of pharmacological treatment and Motivational Interviewing/Cognitive Behavioural Therapy were obtained from Cochrane reviews and meta-analyses. Simulations were used to model the number of deaths under different treatment scenarios. Sensitivity analyses were performed to model the effects of Brief Interventions and to examine the effect of using AD prevalence data obtained from the National Institute for Health and Clinical Excellence. Results In the UK, 320 female and 1,385 male deaths would have been avoided if treatment coverage of pharmacological treatment had been increased to 20%. This decrease in the number of deaths represents 7.9% of all alcohol-attributable deaths (7.0% of all alcohol-attributable deaths for women and 8.1% of all alcohol-attributable deaths for men). If we used lower AD prevalence rates obtained from the National Institute for Health and Clinical Excellence, then treatment coverage of pharmacological treatment in hospitals for 20% of the population with AD would have resulted in the avoidance of 529 deaths in 2004 (99 deaths avoided for women and 430 deaths avoided for men). Conclusions Increasing AD treatment in the UK would have led to a large number of deaths being avoided in 2004. Increased AD treatment rates not only impact mortality but also impact upon the large burden of disability and morbidity attributable to AD, as well as the associated social and economic burdens.

scholarly journals Are former heavy drinkers in the UK less likely to identify as being in recovery compared to those in the USA? A pilot test

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
John A Cunningham ◽  
Alexandra Godinho
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Preliminary Test ◽  
Apparent Difference ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Convenience Sample ◽  
Heavy Drinkers ◽  
The Usa ◽  
The Uk

Abstract Background To provide a preliminary test of the prediction that fewer former heavy drinkers will identify themselves as being in recovery in the UK versus the USA. Methods An online cross-sectional survey was completed by a convenience sample of former heavy drinkers. This sample was identified from participants recruited to complete a questionnaire about alcohol consumption. The recruitment advertisement specified that the participants did not need to drink alcohol. The survey included items assessing self-reported current and past levels of alcohol consumption, alcohol dependence at time of heaviest alcohol consumption (ICD-10 criteria), and questions regarding identifying as currently or ever being in recovery taken from a survey by Kelly et al. (2018). Results Out of 5002 participants who completed the questionnaire, 150 were identified as former heavy drinkers from the UK or the USA. The proportion of participants reporting alcohol dependence, and the proportion of participants reporting past year abstinence, did not differ significantly between the UK and the USA (p = .841 and 0.300 respectively). Compared to participants from the UK, participants in the USA were more likely to report that they had a problem with drinking but now no longer do (24.1 % vs. 56.0 %; p < .001), and that they currently identified (4.2 % vs. 21.2 %; p = .003) or ever identified (7.4 % vs. 30.2 %; p = .001) as being in recovery. Conclusions Identifying as being in recovery appears more common in the USA than the UK among former heavy drinkers. This apparent difference in prevalence may reflect historic differences in treatment services offered in these countries, particularly with respect to the predominance of a 12-step approach in the USA. These findings should be replicated in a representative sample.

scholarly journals Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

2016 ◽  
Author(s):  
Menachem Fromer ◽  
Panos Roussos ◽  
Solveig K Sieberts ◽  
Jessica S Johnson ◽  
David H Kavanagh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Neural Progenitor Cells ◽  
Single Gene ◽  
Genetic Regulation ◽  
Brain Diseases ◽  
Common Variants ◽  
Genetic Associations ◽  
Significant Differential Expression ◽  
Altered Expression

ABSTRACTOver 100 genetic loci harbor schizophrenia associated variants, yet how these common variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating the largest publicly available resource to date of gene expression and its genetic regulation; ∼5 times larger than the latest release of GTEx. Using this resource, we find that ∼20% of the schizophrenia risk loci have common variants that could explain regulation of brain gene expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of FURIN1 in neural progenitor cells derived from human induced pluripotent stem cells produces abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential expression between cases and controls, 44% show some evidence for differential expression. All fold changes are ≤ 1.33, and an independent cohort yields similar differential expression for these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly polygenic, as has been reported in investigations of common and rare genetic variation. Co-expression analyses identify a gene module that shows enrichment for genetic associations and is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic interpretations of genetic liability for schizophrenia and other brain diseases.

Harmful drinking and alcohol dependence

2021 ◽  
pp. 175573802110530
Author(s):  
Sarah Invine
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Alcohol Intake ◽  
Social Norm ◽  
Psychoactive Substances ◽  
Drinking Alcohol ◽  
Harmful Drinking ◽  
The World ◽  
The Uk ◽  
Risk Of Relapse

Alcohol is one of the most popular psychoactive substances in the world, and drinking it is considered a social norm in the UK. The pandemic has increased the potential for hazardous drinking, as well as the risk of relapse from abstinence in those with dependence. This article will discuss the risks associated with drinking alcohol, how to assess alcohol consumption and what interventions can be provided for motivated patients who want to cut their alcohol intake.

The Oral Intake of Organic Germanium, Ge-132, Elevates α-Tocopherol Levels in the Plas-ma and Modulates Hepatic Gene Expression Profiles to Promote Immune Activation in Mice

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0183-0195 ◽  
Author(s):  
Takashi Nakamura ◽  
Tomoya Takeda ◽  
Yoshihiko Tokuji
Keyword(s):  
Gene Expression ◽  
Immune Activation ◽  
Expression Profiles ◽  
Water Soluble ◽  
Alpha Tocopherol ◽  
Hepatic Gene Expression ◽  
Tocopherol Concentration ◽  
Altered Expression ◽  
Atp Production ◽  
Transfer Protein

The common water-soluble organic germanium compound poly-trans-[(2-carboxyethyl) germasesquioxane] (Ge-132) exhibits activities related to immune responses and antioxidant induction. In this study, we evaluated the antioxidative effect of dietary Ge-132 in the plasma of mice. Male ICR mice (seven mice per group) received an AIN-76 diet with 0.05 % Ge-132; three groups received the Ge-132-containing diet for 0, 1 or 4 days. The plasma alpha-tocopherol (α-tocopherol) concentration increased from 6.85 to 9.60 μg/ml after 4 days of Ge-132 intake (p < 0.05). We evaluated the changes in hepatic gene expression related to antioxidative activity as well as in the entire expression profile after one day of Ge-132 intake, using DNA microarray technology. We identified 1,220 genes with altered expression levels greater than 1.5-fold (increased or decreased) as a result of Ge-132 intake, and α-tocopherol transfer protein (Ttpa) gene expression was increased 1.62-fold. Immune activation was identified as the category with the most changes (containing 60 Gene Ontology (GO) term biological processes (BPs), 41 genes) via functional clustering analysis of altered gene expression. Ge-132 affected genes in clusters related to ATP production (22 GO term BPs, 21 genes), lipid metabolism (4 GO term BPs, 38 genes) and apoptosis (5 GO term BPs). Many GO term BPs containing these categories were significantly affected by the Ge-132 intake. Oral Ge-132 intake may therefore have increased plasma α-tocopherol levels by up-regulating α-tocopherol transfer protein (Ttpa) gene expression.

Symptoms of Alcohol Dependence Predict Suicide Ideation Among Alaskan Undergraduates

Crisis ◽  
2016 ◽  
Vol 37 (3) ◽  
pp. 232-235 ◽  
Author(s):  
Christopher R. DeCou ◽  
Monica C. Skewes
Keyword(s):  
Depressive Symptoms ◽  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Suicide Ideation ◽  
Alcohol Problems ◽  
Future Research ◽  
Causal Mechanism ◽  
Students At Risk ◽  
The Relationship ◽  
Alcohol Related Problems

Abstract. Background: Previous research has demonstrated an association between alcohol-related problems and suicidal ideation (SI). Aims: The present study evaluated, simultaneously, alcohol consequences and symptoms of alcohol dependence as predictors of SI after adjusting for depressive symptoms and alcohol consumption. Method: A sample of 298 Alaskan undergraduates completed survey measures, including the Young Adult Alcohol Consequences Questionnaire, the Short Alcohol Dependence Data Questionnaire, and the Beck Depression Inventory – II. The association between alcohol problems and SI status was evaluated using sequential logistic regression. Results: Symptoms of alcohol dependence (OR = 1.88, p < .05), but not alcohol-related consequences (OR = 1.01, p = .95), emerged as an independent predictor of SI status above and beyond depressive symptoms (OR = 2.39, p < .001) and alcohol consumption (OR = 1.08, p = .39). Conclusion: Alcohol dependence symptoms represented a unique risk for SI relative to alcohol-related consequences and alcohol consumption. Future research should examine the causal mechanism behind the relationship between alcohol dependence and suicidality among university students. Assessing the presence of dependence symptoms may improve the accuracy of identifying students at risk of SI.

scholarly journals Rewired Pathways and Disrupted Pathway Crosstalk in Schizophrenia Transcriptomes by Multiple Differential Coexpression Methods

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 665
Author(s):  
Hui Yu ◽  
Yan Guo ◽  
Jingchun Chen ◽  
Xiangning Chen ◽  
Peilin Jia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Focal Adhesion ◽  
Biological Pathways ◽  
Postmortem Brain ◽  
Rna Seq ◽  
Hub Genes ◽  
Differential Coexpression ◽  
Pathway Crosstalk ◽  
Microarray Datasets ◽  
Transcriptomic Studies

Transcriptomic studies of mental disorders using the human brain tissues have been limited, and gene expression signatures in schizophrenia (SCZ) remain elusive. In this study, we applied three differential co-expression methods to analyze five transcriptomic datasets (three RNA-Seq and two microarray datasets) derived from SCZ and matched normal postmortem brain samples. We aimed to uncover biological pathways where internal correlation structure was rewired or inter-coordination was disrupted in SCZ. In total, we identified 60 rewired pathways, many of which were related to neurotransmitter, synapse, immune, and cell adhesion. We found the hub genes, which were on the center of rewired pathways, were highly mutually consistent among the five datasets. The combinatory list of 92 hub genes was generally multi-functional, suggesting their complex and dynamic roles in SCZ pathophysiology. In our constructed pathway crosstalk network, we found “Clostridium neurotoxicity” and “signaling events mediated by focal adhesion kinase” had the highest interactions. We further identified disconnected gene links underlying the disrupted pathway crosstalk. Among them, four gene pairs (PAK1:SYT1, PAK1:RFC5, DCTN1:STX1A, and GRIA1:MAP2K4) were normally correlated in universal contexts. In summary, we systematically identified rewired pathways, disrupted pathway crosstalk circuits, and critical genes and gene links in schizophrenia transcriptomes.

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