Project description:<p>This study includes SSADDA (Semi Structured Assessment for Drug Dependence and Alcoholism) assessed subjects (mostly unrelated, but including some affected sibling pairs) recruited in the course of several substance dependence genetics projects. The sample includes 1889 African-American (AA) subjects and 1020 European-American (EA) subjects. Among the AAs, 1397 meet DSM-IV criteria for alcohol dependence and 491 are controls. Among the EAs, 1010 meet the criteria for alcohol dependence and 9 are controls. (One in each population meets criteria for alcohol abuse and not dependence, and is therefore counted in neither category.) Although alcohol dependence is the major focus, the sample is informative also for cocaine, nicotine, and opioid dependence.</p>
Project description:The prefrontal cortex is a crucial regulator of escalation of alcohol drinking, dependence, and other behavioral criteria associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms mediating the escalation of alcohol use and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) on ~150,000 single nuclei from the medial prefrontal cortex (mPFC) obtained from C57BL/6J mice exposed to the chronic intermittent ethanol exposure (CIE) paradigm which models phenotypes associated with alcohol dependence. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Here, we present a comprehensive atlas of cell-type specific alcohol dependence related gene expression changes in the mPFC.
Project description:Several studies have shown an association of alcohol dependence with DNA methylation, suggesting that environmentally-induced changes on epigenomic variation may play an important role in alcohol dependence. In the present study, we analyzed genome-wide DNA methylation profiles of purified CD3+ T-cells from pre- and post-treatment alcohol dependent patients, as well as closely matched healthy controls. We identified 59 differentially methylated CpG sites comparing patients prior to treatment with healthy controls and were able to confirm 8 of those sites in additional analyses for differentially methylated regions. Comparing patients before and after a 3-week alcohol treatment program we revealed another unique set of 48 differentially methylated CpG sites. Additionally, we found that the mean global DNA methylation was significantly lower in patients prior to treatment compared to controls, but reverted back to levels similar to controls after treatment. We validated top-ranked hits derived from the epigenome-wide analysis by pyrosequencing and further replicated two of them in an independent cohort and confirmed differential DNA methylation of HECW2 and SRPK3 in whole blood. This study is the first to show widespread DNAm variation in a disease-relevant blood cell type and implicates HECW2 and SRPK3 DNAm as promising candidates to follow up in future studies.
Project description: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.
Project description:<p>This study includes SSADDA (Semi Structured Assessment for Drug Dependence and Alcoholism) assessed subjects (mostly unrelated, but including some affected sibling pairs) recruited in the course of several substance dependence genetics projects. The sample includes 1889 African-American (AA) subjects and 1020 European-American (EA) subjects. Among the AAs, 1397 meet DSM-IV criteria for alcohol dependence and 491 are controls. Among the EAs, 1010 meet the criteria for alcohol dependence and 9 are controls. (One in each population meets criteria for alcohol abuse and not dependence, and is therefore counted in neither category.) Although alcohol dependence is the major focus, the sample is informative also for cocaine, nicotine, and opioid dependence.</p>
Project description:Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL17 Receptor A (IL17ra-/-), or pharmacological blockade of IL17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice, and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL17A positively correlated with the alcohol use in excessive drinkers, and was further increased in patients with ALD as compared to healthy individuals. Our data suggest that IL17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL17A may provide a novel strategy for treatment of alcohol-induced pathology.
Project description:The goal of this study was to identify molecular mechanisms regulated by pharmacological and placebo effects of binge-drinking at a transcriptome-wide level. We performed RNA-seq on PBMC samples collected from healthy heavy social drinkers (N=18) enrolled in an upto 12-day in-patient, randomized, double-blind, cross-over human laboratory trial testing three alcohol doses: Placebo, medium (0.05g/kg (men), 0.04g/kg (women)), and binge (1g/kg (men), 0.9g/kg (women)), administered in three 4-day experiments, separated by minimum of 7-day washout periods. Effects of beverage doses on differential expression of genes (DEGs) within each experiment compared to its own baseline, across experimental sequences in which each beverage dose was administered, and responsiveness to regular alcohol compared to placebo assessing pharmacological effects of alcohol were analyzed.