We hypothesized that cross-generational effects of alcohol exposure could alter DNA methylation and expression of the
oncogene and
tumor suppressor gene that drive cancer development.
DNA methylation ...of the
and
genes was tested in samples from young participants (Mean age of 13.4 years).
Controlling for both personal use and maternal use of substances during pregnancy, familial alcohol dependence was associated with hypomethylation of CpG sites in the
promoter region and hypermethylation of the
gene.
The results suggest that ancestral exposure to alcohol can have enduring effects that impact epigenetic processes such as DNA methylation that controls expression of genes that drive cancer development such as
and
.
Genome‐wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which ...may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM‐IV AD (primary analysis), DSM‐IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans‐ancestral meta‐analyses combined these results with data from 3175 (585 families) African‐American (AA) individuals from COGA. In the EA GWAS, three loci were genome‐wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E−11) and Desire to cut drinking (P = 1.21E−11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E−09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E−08). In the trans‐ancestral meta‐analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome‐wide significant: rs61826952 (chromosome 1, DSM‐IV AD, P = 8.42E−11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E−08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%‐1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss − gain; P = .0037) and reward‐related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.
We performed genome‐wide association studies (GWAS) of DSM‐IV alcohol dependence (AD), AD criterion count, and individual criteria among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA); and conducted trans‐ancestral meta‐analyses combined EA results with data from 3175 (585 families) African‐American individuals from COGA. Three loci in EA GWAS and three loci in meta‐analysis were genome‐wide significant with multiple phenotypes. Except the well‐known rs1229984 in ADH1B, all other findings are novel. Two findings were replicated in independent datasets. Polygenic risk scores derived from the EA AD GWAS predicted AD in two EA datasets (P < .01). Two findings were associated with differential central evoked theta power (P = .0037) and reward‐related ventral striatum reactivity (P = .008), respectively.
Chronic excessive alcohol consumption induces cognitive impairments mainly affecting executive functions, episodic memory, and visuospatial capacities related to multiple brain lesions. These ...cognitive impairments not only determine everyday management of these patients, but also impact on the efficacy of management and may compromise the abstinence prognosis. Maintenance of lasting abstinence is associated with cognitive recovery in these patients, but some impairments may persist and interfere with the good conduct and the efficacy of management. It therefore appears essential to clearly define neuropsychological management designed to identify and evaluate the type and severity of alcohol-related cognitive impairments. It is also essential to develop cognitive remediation therapy so that the patient can fully benefit from the management proposed in addiction medicine units.
Our laboratory has previously shown that chronic ethanol exposure elicits enhanced working memory performance in female, but not male, adult Sprague-Dawley rats, indicative of a fundamental sex ...difference in cortical plasticity. Recent studies have furthermore revealed that females display markedly reduced HCN-mediated channel activity in inhibitory Martinotti interneurons after chronic ethanol exposure that is similarly not observed in males. From these observations we hypothesized that alcohol elicits facilitated working memory performance via down-regulation of these channels’ activity specifically within interneurons. To test this hypothesis, we employed a Pol-II compatible shRNA expression system to elicit targeted knockdown of HCN channel activity in these cells, and measured performance on a delayed Non-Match-to-Sample (NMS) T-maze test to gauge effects on working memory performance. A significant baseline enhancement of working memory performance with HCN channel knockdown was observed, indicative of a critical role for interneuron-expressed HCNs in maintaining optimal cortical network activity during cognitively-demanding tasks. Consistent with previous observations, ethanol exposure resulted in enhanced NMS T-maze performance, however elevated working memory performance was observed in both scram- and hcn-shRNA infected groups after alcohol administration. We therefore conclude that interneuron-expressed HCN channels, despite representing a minor population of total cortical HCN expression, contribute substantially to maintaining working memory processes. Downregulated HCN channel activity, though, does not alone appear sufficient to manifest alcohol-induced enhancement of working memory performance observed in female rats during acute withdrawal.
•Interneuron-Selective HCN channel knockdown in prelimbic cortex of female rats enhanced working memory performance in female rats.•This effect mimicked adaptations to chronic ethanol exposure where HCN channels were reduced and working memory performance was enhanced.•HCN knockdown was accomplished using Pol II promotors to reduce HCN in somatostatin -positive cells and verified by electrophysiological characteristics of the neurons.•Cortical HCN expression in interneurons contributes to working memory performance and may contribute to effects of chronic ethanol exposure of T maze performance.
The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, and other behavioral phenotypes associated with AUD. Comprehensive identification of cell-type specific ...transcriptomic changes in alcohol dependence will improve our understanding of mechanisms underlying the excessive alcohol use associated with alcohol dependence and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) and Visium spatial gene expression profiling on the medial prefrontal cortex (mPFC) obtained from C57BL/6 J mice exposed to the two-bottle choice-chronic intermittent ethanol (CIE) vapor exposure (2BC-CIE, defined as dependent group) paradigm which models phenotypes of alcohol dependence including escalation of alcohol drinking. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Dysregulated modules and their hub genes suggest novel understudied targets for studying molecular mechanisms contributing to the alcohol dependence state. A subtype of inhibitory neurons was the most alcohol-sensitive cell type and contained a downregulated gene co-expression module; the hub gene for this module is Cpa6, a gene previously identified by GWAS to be associated with excessive alcohol consumption. We identified an astrocytic Gpc5 module significantly upregulated in the alcohol-dependent group. To our knowledge, there are no studies linking Cpa6 and Gpc5 to the alcohol-dependent phenotype. We also identified neuroinflammation related gene expression changes in multiple cell types, specifically enriched in microglia, further implicating neuroinflammation in the escalation of alcohol drinking. Here, we present a comprehensive atlas of cell-type specific alcohol dependence mediated gene expression changes in the mPFC and identify novel cell type-specific targets implicated in alcohol dependence.
Ever since 2018 France has been the only country to approve the gamma aminobutyric acid type B (GABA-B) receptor agonist baclofen for alcohol dependence. This authorization follows a ten-year period ...of intensive off-label use during which baclofen was used in doses of up to 300 and even 400mg per day to support the gradual reduction of alcohol consumption in patients suffering from alcohol dependence. However, in international clinical trials, baclofen has mainly been studied to support the maintenance of abstinence. The French use of baclofen was therefore somewhat atypical as it paved the way for drug-supported approaches to reducing alcohol consumption, even before nalmefene was marketed. In line with this specific use of baclofen, approval was granted only for alcohol reduction support. However, a recent Cochrane systematic review and meta-analysis by Agabio et al. found significant efficacy only for abstinence maintenance, while no significant effect was found on alcohol reduction outcomes and no dose-response relationship was identified in the analyses. The safety of baclofen was judged to be good. Based on these substantial new results, the Société française d’alcoologie (SFA) now considers that baclofen should also be approved for the maintenance of abstinence. The extension of approval should not lead to the removal of the initial indication or the possibility of using high doses, as some patients have found this therapeutic regimen particularly useful for them. France, which has been a open skies national laboratory on the use of baclofen in alcohol dependence for over ten years, should let this original therapeutic option available to patients. However, it should update the regulatory framework defining the main conditions of access to treatment for patients based on the latest and highest scientific evidence.
Depuis 2018, et jusqu’à présent, la France est le seul pays à avoir accordé une autorisation de mise sur le marché au baclofène, agoniste des récepteurs de l’acide gamma aminobutyrique de type B (GABA-B), dans la dépendance à l’alcool. Cette autorisation fait suite à une période de dix ans d’usage hors AMM intensif du baclofène, au cours de laquelle les prescriptions pouvaient atteindre des doses de 300, voire 400 mg par jour, pour accompagner la réduction progressive de la consommation d’alcool chez les patients. Par contraste, dans les essais cliniques internationaux, le baclofène avait essentiellement été étudié dans le maintien de l’abstinence. L’utilisation française du baclofène a donc été quelque peu atypique, puisqu’elle a ouvert la voie à des approches de réduction de la consommation d’alcool soutenues par des médicaments, avant même la mise sur le marché du nalméfène. Conformément à cette utilisation particulière du baclofène dans le pays, l’AMM n’a été accordée que pour l’aide à la réduction de la consommation d’alcool. Cependant, une récente revue systématique et méta-analyse Cochrane réalisée par Agabio et al., a retrouvé une efficacité significative uniquement pour le maintien de l’abstinence, alors qu’aucun effet n’a été constaté sur les paramètres de réduction de la consommation d’alcool, et qu’aucune relation dose–effet n’a été mise en évidence. La sécurité du baclofène a été jugée bonne. Sur la base de ces nouveaux résultats importants, la Société française d’alcoologie (SFA) estime que l’AMM du baclofène devrait être étendue à l’indication de maintien de l’abstinence. Cette révision d’AMM ne devrait pas mener à la suppression de l’indication initiale et de la possibilité d’utiliser des doses élevées, car certains patients ont pu trouver ce schéma thérapeutique particulièrement utile pour eux. La France, qui constitue depuis plus de dix ans un laboratoire national « à ciel ouvert » sur l’utilisation du baclofène dans l’alcoolodépendance, devrait laisser cette option thérapeutique originale à la disposition des patients, mais devrait aussi mettre à jour le cadre réglementaire définissant les principales conditions d’accès au traitement pour les patients, sur la base des preuves scientifiques les plus récentes et les plus élevées.
Alcohol dependence during COVID-19 lockdowns Killgore, William D.S.; Cloonan, Sara A.; Taylor, Emily C. ...
Psychiatry research,
February 2021, 2021-02-00, Volume:
296
Journal Article
Peer reviewed
Open access
•Many people were ordered to shelter-in-place during the COVID-19 pandemic.•Harmful alcohol use increased notably during the first six months of the pandemic.•Increased alcohol use was greatest for ...those under lockdown/stay-at-home orders.•Excessive pandemic-drinking is concerning, as it may lead to other harmful behaviors.
To determine whether the past half-year of COVID-19-related lockdowns, stay-at-home orders, and social isolation were associated with changes in high-risk alcohol use, a total of 5,931 individuals completed the Alcohol Use Disorders Identification Test (AUDIT) at one of six time points from April through September 2020. Over the 6-month period, hazardous alcohol use and likely dependence increased month-by-month for those under lockdowns compared to those not under restrictions. This increase in harmful alcohol use and related behaviors is likely to have prolonged adverse psychosocial, interpersonal, occupational, and health impacts as the world attempts to recover from the pandemic crisis.
Introduction
Scotland implemented a minimum price per unit of alcohol (MUP) of £0.50 in May 2018 (1 UK unit = 10 mL/8 g ethanol). Some stakeholders expressed concerns about the policy having ...potential negative consequences for people with alcohol dependence. This study aimed to investigate anticipated impacts of MUP on people presenting to alcohol treatment services in Scotland before policy implementation.
Methods
Qualitative interviews were conducted with 21 people with alcohol dependence accessing alcohol treatment services in Scotland between November 2017 and April 2018. Interviews examined respondents' current and anticipated patterns of drinking and spending, effects on their personal life, and their views on potential policy impact. Interview data were thematically analysed using a constant comparison method.
Results
Three key themes were identified: (i) strategies used to manage the cost of alcohol and anticipated responses to MUP; (ii) broader effects of MUP; and (iii) awareness and preparedness for MUP. Respondents expected to be impacted by MUP, particularly those on low incomes and those with more severe dependence symptoms. They anticipated using familiar strategies including borrowing and reprioritising spending to keep alcohol affordable. Some respondents anticipated negative consequences. Respondents were sceptical about the short‐term benefits of MUP for current drinkers but felt it might prevent harm for future generations. Respondents had concerns about the capacity of treatment services to meet support needs.
Discussion and conclusions
People with alcohol dependence identified immediate concerns alongside potential long‐term benefits of MUP before its introduction. They also had concerns over the preparedness of service providers.
Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, ...most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol EtOH) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.
The genes that have the largest impact on alcohol consumption and Alcohol Use Disorders are alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2); both work by altering the rate of ethanol metabolism to at least transiently elevate acetaldehyde. Different functional variations are important in different populations. ADH1B and ADH4 have also been implicated, but linkage disequilibrium complicates analyses, and other variants may only be proxies for the functional variants.
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