Etiology Of Alcohol Use Disorder Research Articles

Alcohol and common ground: The effects of intoxication on linguistic markers of shared understanding during social exchange.

Most alcohol consumption takes place in social contexts, and the belief that alcohol enhances social interactions has been identified as among the more robust predictors of alcohol use disorder (AUD) development. Yet, we know little of how alcohol affects mental representations of others-what we share and do not share-nor the extent to which intoxication might impact the development of shared understanding (i.e., common ground) between interaction partners. Employing a randomized experimental design and objective linguistic outcome measures, we present two studies examining the impact of alcohol consumption on the development and use of common ground. In Study 1, groups of strangers or friends were administered either alcohol (target Breath Alcohol Content = .08%) or a control beverage, following which they completed a task requiring them to develop a shared language to describe ambiguous images and then describe those images to either a knowledgeable or a naïve partner. The same procedures were completed in Study 2 using a within-subjects alcohol administration design and all-stranger groups. Study 1 findings did not reach significance but suggested that alcohol may facilitate common ground development selectively among stranger groups. This effect emerged as significant in the context of the within-subjects design of Study 2, b = -0.19, p = .007, with participants demonstrating greater facility in establishing common ground during alcohol versus control sessions. Results suggest that alcohol facilitates the development of shared linguistic understanding in novel social spaces, indicating common ground as one potential mechanism to consider in our broader examination of alcohol reinforcement and AUD etiology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The collaborative study on the genetics of alcoholism: Genetics.

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.

Genetic and Cultural Transmission of Alcohol Use Disorder in Swedish Twin Pedigrees.

Using Swedish nationwide registry data, we investigated the contribution of genetic and environmental risk factors to the etiology of alcohol use disorder (AUD) by extended twin pedigree modeling. AUD was defined using public inpatient, outpatient, prescription, and criminal records. Three-generational pedigrees were selected for index individuals born between 1980 and 1990, obtained from the national twin and genealogical registers, whose parents were twins. Relatives of the twins included in the pedigrees were their parents, siblings, spouses, and children. Genetic structural equation modeling was applied to the population-based data on AUD, using OpenMx, with age used as a covariate. Analyses including up to 162,469 individuals in 18,971 pedigrees estimated AUD prevalence at 5%-12% in men and 2%-5% in women. Results indicated substantial heritability (about 50%-60%), of which a portion upwards of 5% was attributable to the consequences of assortative mating. Contributions of shared environmental factors to AUD, which represent a mix of within- and cross-generational effects, appeared to be moderate (about 10%-20%). Unique environment accounted for the remaining variance (about 20%-30%). Sex differences in the magnitude of the variance components suggested higher heritability in men and correspondingly higher shared environmental contributions in women. Using objective registry data, we found that AUD is highly heritable. Furthermore, shared environmental factors contributed significantly to the liability of AUD in both men and women.

A social contextual review of the effects of alcohol on emotion

Drinking and drinking problems are complex phenomena. Understanding the etiology of alcohol use disorder requires consideration of biological, psychological, and social processes. It is our view that the last of these dimensions is just beginning to receive adequate scrutiny. In this selective review, we discuss the concept of a biopsychosocial analysis of the effects of alcohol. After briefly addressing biological and psychological research on alcohol's emotional effects, we bid to make a case for the vital role that social processes play in understanding why people drink. The bulk of the paper describes research illustrating the contributions that a social psychological perspective can make to advance understanding of the rewarding effects of alcohol. Overall, studies incorporating social contexts have revealed reliable evidence that alcohol enhances emotional experience in many social environments and have identified socio-contextual variables that moderate responses to alcohol. Further, these studies have broadened the scope of constructs thought to be socially rewarding, including social bonding, relationship functioning, and humor enjoyment. Our analysis concludes by identifying research areas we believe would profit from additional research.

Long Non-Coding RNAs: The New Frontier into Understanding the Etiology of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a complex, chronic, debilitating condition impacting millions worldwide. Genetic, environmental, and epigenetic factors are known to contribute to the development of AUD. Long non-coding RNAs (lncRNAs) are a class of regulatory RNAs, commonly referred to as the “dark matter” of the genome, with little to no protein-coding potential. LncRNAs have been implicated in numerous processes critical for cell survival, suggesting that they play important functional roles in regulating different cell processes. LncRNAs were also shown to display higher tissue specificity than protein-coding genes and have a higher abundance in the brain and central nervous system, demonstrating a possible role in the etiology of psychiatric disorders. Indeed, genetic (e.g., genome-wide association studies (GWAS)), molecular (e.g., expression quantitative trait loci (eQTL)) and epigenetic studies from postmortem brain tissues have identified a growing list of lncRNAs associated with neuropsychiatric and substance use disorders. Given that the expression patterns of lncRNAs have been associated with widespread changes in the transcriptome, including methylation, chromatin architecture, and activation or suppression of translational activity, the regulatory nature of lncRNAs may be ubiquitous and an innate component of gene regulation. In this review, we present a synopsis of the functional impact that lncRNAs may play in the etiology of AUD. We also discuss the classifications of lncRNAs, their known functional roles, and therapeutic advancements in the field of lncRNAs to further clarify the functional relationship between lncRNAs and AUD.

Emotion Regulation Difficulties and Childhood Trauma are Associated with Alcohol Use Severity: A Comparison with Healthy Volunteers

Objective: Emotion regulation difficulties and the effect of childhood traumas on the etiology of alcohol use disorder are an important topic in the literature. This study aimed to evaluate patients with alcohol use disorder in terms of emotional control and childhood trauma and the difficulty in trauma and emotion regulation as a risk factor. Methods: In this study, 37 patients with alcohol use disorder (AUD) and 37 healthy volunteers were included. The participants were assessed with a 35-item sociodemographic data form, Severity of Alcohol Dependence Questionnaire (SADQ-C), Childhood Trauma Questionnaire (CTQ-28), and Difficulties in Emotion Regulation Scale (DERS). All participants were interviewed based on DSM-5. Results: Participants with AUD had more difficulty in regulating emotions in all areas. clarity, awareness, impulse, nonacceptance, objectives, and strategies were deteriorated (p < 0.05). Patients with AUD had more childhood traumas. All trauma types, especially physical neglect and emotional abuse were more common in participants with AUD. Assessment of the traumas and emotion regulation revealed that emotional abuse increased the risk of AUD by 1.6 times (95% CI 1.025–2.801) and maladaptive emotion regulation strategies are linked to addiction severity.Conclusion: The maladaptive emotional strategies of patients with AUD were worse than those of healthy volunteers. Patients with AUD experienced more childhood traumas. Particularly, emotional abuse increased the risk of AUD. As a result, childhood traumas were more severe in patients with AUD, and they adversely affected emotion regulation strategies and increased addiction severity.

The effect of alcohol on mood among males drinking with a platonic friend.

Despite the social nature of most drinking experiences, prior work has largely failed to incorporate social context into the study of alcohol's effects on emotion. The present study provides an initial test of the effect of alcohol on mood among platonic friends drinking together in a non-stress setting. We hypothesized that subjects would report more positive postdrink mood after consuming alcohol than after consuming a nonalcoholic control beverage. Dyads of platonic male friends (n=36; 55.55% White, 38.88% Asian, 5.55% Black) attended two laboratory-based experimental sessions, wherein their drink conditions (alcohol vs. no alcohol control) were randomized by dyad and counter-balanced across sessions. They reported their mood before and after consuming their beverages together, using the Positive and Negative Affect Schedule and an 8-item mood measure. As hypothesized, alcohol enhanced positive mood ( =0.26, p<0.01). Although in the expected direction, the effect of alcohol on negative mood was not significant ( =-0.12, p=0.17). Post hoc analyses revealed that alcohol yielded greater increases in both stimulation ( , p=0.00) and sedation ( , p=0.00) as compared to the control condition. This study highlights the positive mood-enhancing and broader subjective effects of alcohol when drinking with a platonic friend and encourages further consideration of friendship contexts in the examination of alcohol's effects when developing models of the etiology of alcohol use disorder.

Ethanol-Induced Adaptations to Inhibitory Microcircuits in the Mouse Prefrontal Cortex

Prefrontal cortex (PFC) dysfunction is a central component of the etiology of alcohol use disorder (AUD) and other addictions. While mechanistic studies have revealed many adaptations to PFC pyramidal cells in models of binge drinking and ethanol dependence, relatively little research has focused on alterations to defined populations of inhibitory interneurons.

PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder.

Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to control or stop alcohol intake and is associated with organ damage including alcohol-associated liver disease (ALD) and progressive neurodegeneration. The etiology of AUD is complex, but organ injury due to chronic alcohol use can be partially attributed to systemic and local inflammation along the gut-liver-brain axis. Excessive alcohol use can result in translocation of bacterial products into circulation, increased expression of pro-inflammatory cytokines, and activation of immune cells, including macrophages and/or microglia in the liver and brain. One potential mediator of this alcohol-induced inflammation is proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is primarily known for its regulation of plasma low-density lipoprotein cholesterol but has more recently been shown to influence inflammatory responses in the liver and brain. In rodent and post-mortem brain studies, chronic alcohol use altered methylation of the PCSK9 gene and increased expression of PCSK9 in the liver and cerebral spinal fluid. Additionally, PCSK9 inhibition in a rat model of ALD attenuated liver inflammation and steatosis. PCSK9 may play an important role in alcohol-induced pathologies along the gut-liver-brain axis and may be a novel therapeutic target for AUD-related liver and brain inflammation.

Understanding the Progression from Early Alcohol Use Experimentation to Alcohol Use Disorder: Testing Vulnerability by Experience Interactions Using a Two-Part Latent Growth Curve Model.

Most adolescents experiment with alcohol, but a smaller percentage advance to heavy alcohol use (AU) and AU disorder (AUD). Understanding for whom and how early risk leads to AUD is of interest to prevention, treatment, and etiology of AUD. Informed by developmental and behavioral neuroscience theory, the current study tested whether temperament (effortful control, surgency, and negative affect), peer AU (multi-reporter), and AU with parents' permission interacted to distinguish youth who experiment with alcohol from those who escalate to AUD. Community adolescents (N = 765, 53% female) were assessed annually for seven years (Mage = 11.8, range: 10-13 at Year 1; Mage = 18.7; range = 17-20 at year 7). Temperament by early experience interactions were expected to predict amount of AU. Amount of AU was expected to mediate the relationship between the interactions and AUD symptoms (assessed at Years 3 and 7, Mage = 13.8 and 18.7) above and beyond a range of confounds (e.g., problem behavior and parental AU and AUD). Supporting hypotheses, effortful control and surgency interacted with AU with parents' permission and peer AU, respectively, to predict higher amount of AU (R2 = 0.47) and AUD symptoms (R2 = 0.03). Results support developmental and behavioral neuroscience theory. High surgency and low effortful control in conjunction with peer AU and AU with parents' permission were associated with large effects on AU and moderate mediated effects through AU to AUD. AU with parents' permission was risky at low and high effortful control and protective when peers used alcohol.

Epigenetics of alcohol use disorder-A review of recent advances in DNA methylation profiling.

Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there is a heritable component, the etiology of AUD is complex and can involve environmental exposures like trauma and can be associated with many different patterns of alcohol consumption. Epigenetic modifications, which can mediate the influence of genetic variants and environmental variables on gene expression, have emerged as an important area of AUD research. Over the past decade, the number of studies investigating AUD and DNA methylation, a form of epigenetic modification, has grown rapidly. Yet we are still far from understanding how DNA methylation contributes to or reflects aspects of AUD. In this paper, we reviewed studies of DNA methylation and AUD and discussed how the field has evolved. We found that global DNA and candidate DNA methylation studies did not produce replicable results. To assess whether findings of epigenome‐wide association studies (EWAS) were replicated, we aggregated significant findings across studies and identified 184 genes and 15 gene ontological pathways that were differentially methylated in at least two studies and four genes and three gene ontological pathways that were differentially methylated in three studies. These genes and pathways repeatedly found enrichment of immune processes, which is in line with recent developments suggesting that the immune system may be altered in AUD. Finally, we assess the current limitations of studies of DNA methylation and AUD and make recommendations on how to design future studies to resolve outstanding questions.

Tyramine synthesis, vesicular packaging, and the SNARE complex function coordinately in astrocytes to regulate Drosophila alcohol sedation.

Identifying mechanisms underlying alcohol-related behaviors could provide important insights regarding the etiology of alcohol use disorder. To date, most genetic studies on alcohol-related behavior in model organisms have focused on neurons, leaving the causal roles of glial mechanisms less comprehensively investigated. Here, we report our studies on the role of Tyrosine decarboxylase 2 (Tdc2), which converts tyrosine to the catecholamine tyramine, in glial cells in Drosophila alcohol sedation. Using genetic approaches that drove transgene expression constitutively in all glia, constitutively in astrocytes and conditionally in glia during adulthood, we found that knockdown and overexpression of Tdc2, respectively, increased and decreased the sensitivity to alcohol sedation in flies. Manipulation of the genes tyramine β-hydroxylase and tyrosine hydroxylase, which respectively synthesize octopamine and dopamine from tyramine and tyrosine, had no discernable effect on alcohol sedation, suggesting that Tdc2 affects alcohol sedation by regulating tyramine production. We also found that knockdown of the vesicular monoamine transporter (VMAT) and disruption of the SNARE complex in all glia or selectively in astrocytes increased sensitivity to alcohol sedation and that both VMAT and the SNARE complex functioned downstream of Tdc2. Our studies support a model in which the synthesis of tyramine and vesicle-mediated release of tyramine from adult astrocytes regulates alcohol sedation in Drosophila. Considering that tyramine is functionally orthologous to norepinephrine in mammals, our results raise the possibility that gliotransmitter synthesis release could be a conserved mechanism influencing behavioral responses to alcohol as well as alcohol use disorder.

Childhood trauma and post-trauma environment affect fear memory and alcohol use differently in male and female mice

BackgroundChildhood trauma is associated with the development of adult mental health and substance use disorders, with females generally being more at risk. Alcohol is commonly used for coping with trauma, and alcohol use disorder (AUD) affects ∼14.4 million adult Americans annually. Research investigating sex differences in the environmental modification of anxiety and alcohol use following childhood trauma will extend our understanding of the etiology of AUD. Here, we sought to model the interacting effects of a single-episode late childhood trauma with post-trauma environment on adult alcohol use using male and female mice. MethodsC57Bl6/J mice (d22) exposed to predator odor (TMT) or water were reared in standard environments (SE) or environmental enrichment (EE). Mice were assessed for adolescent anxiety and conditioned fear, and for adult alcohol use in a limited access, response non-contingent, alcohol exposure paradigm. ResultsA single exposure to predator odor was an effective stressor, inducing long-term sex-dependent changes in conditioned fear and alcohol behaviors that interacted with post-trauma environment. Adolescent EE females showed more conditioned freezing to the trauma-associated context. Adult EE mice consumed less total alcohol than SE mice. However, alcohol use across time differed for males and females. Exposure to a childhood stressor increased alcohol use significantly in females, but not males. EE males, but not EE females, drank less than SE counterparts. ConclusionsFindings from this model recapitulate greater vulnerability to childhood trauma in females and support sex differences in post-trauma development of conditioned fear and alcohol use that are modified by environment.

Contrasting sex-dependent adaptations to synaptic physiology and membrane properties of prefrontal cortex interneuron subtypes in a mouse model of binge drinking

Alcohol use disorder (AUD) affects all sexes, however women who develop AUD may be particularly susceptible to cravings and other components of the disease. While many brain regions are involved in AUD etiology, proper prefrontal cortex (PFC) function is particularly important for top-down craving management and the moderation of drinking behaviors. Essential regulation of PFC output is provided by local inhibitory interneurons, yet how drinking affects interneuron physiology remains poorly understood, particularly in female individuals. To address this gap, we generated fluorescent reporter transgenic mice to label the two major classes of interneuron in deep layer prelimbic PFC, based on expression of parvalbumin (PV-IN) or somatostatin (SST-IN). We then interrogated PV-IN and SST-IN membrane and synaptic physiology in a rodent model of binge drinking. Beginning in late adolescence, mice received 3–4 weeks of intermittent access (IA) ethanol. We prepared acute brain slices one day after the last drinking session. PV-INs but not SST-INs from IA ethanol mice displayed increased excitability relative to controls, regardless of sex. On the contrary, synaptic adaptations to PV-INs differed based on sex. While drinking decreased excitatory synaptic strength onto PV-INs from female mice, PV-INs from IA ethanol male mice exhibited potentiated excitatory transmission relative to controls. In contrast, decreased synaptic strength onto SST-INs was observed following IA ethanol in all groups of mice. Together, these findings illustrate novel sex differences in drinking-related PFC pathophysiology. Discovering means to restore PV-IN and SST-IN dysfunction following extended drinking provides opportunities for developing new treatments for all AUD patients.

Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala.

Excessive serotonin (5-HT) signaling plays a critical role in the etiology of alcohol use disorder. The central nucleus of the amygdala (CeA) is a key player in alcohol-dependence associated behaviors. The CeA receives dense innervation from the dorsal raphe nucleus, the major source of 5-HT, and expresses 5-HT receptor subtypes (e.g., 5-HT2C and 5-HT1A) critically linked to alcohol use disorder. Notably, the role of 5-HT regulating rat CeA activity in alcohol dependence is poorly investigated. Here, we examined neuroadaptations of CeA 5-HT signaling in adult, male Sprague Dawley rats using an established model of alcohol dependence (chronic intermittent alcohol vapor exposure), ex vivo slice electrophysiology and ISH. 5-HT increased frequency of sIPSCs without affecting postsynaptic measures, suggesting increased CeA GABA release in naive rats. In dependent rats, this 5-HT-induced increase of GABA release was attenuated, suggesting blunted CeA 5-HT sensitivity, which partially recovered in protracted withdrawal (2 weeks). 5-HT increased vesicular GABA release in naive and dependent rats but had split effects (increase and decrease) after protracted withdrawal indicative of neuroadaptations of presynaptic 5-HT receptors. Accordingly, 5-HT abolished spontaneous neuronal firing in naive and dependent rats but had bidirectional effects in withdrawn. Alcohol dependence and protracted withdrawal did not alter either 5-HT1A-mediated decrease of CeA GABA release or Htr1a expression but disrupted 5-HT2C-signaling without affecting Htr2c expression. Collectively, our study provides detailed insights into modulation of CeA activity by the 5-HT system and unravels the vulnerability of the CeA 5-HT system to chronic alcohol and protracted withdrawal.SIGNIFICANCE STATEMENT Elevated GABA signaling in the central nucleus of the amygdala (CeA) underlies key behaviors associated with alcohol dependence. The CeA is reciprocally connected with the dorsal raphe nucleus, the main source of serotonin (5-HT) in the mammalian brain, and excessive 5-HT signaling is critically implicated in the etiology of alcohol use disorder. Our study, using a well-established rat model of alcohol dependence, ex vivo electrophysiology and ISH, provides mechanistic insights into how both chronic alcohol exposure and protracted withdrawal dysregulate 5-HT signaling in the CeA. Thus, our study further expands our understanding of CeA cellular mechanisms involved in the pathophysiology of alcohol dependence and withdrawal.

The Role of Stress, Trauma, and Negative Affect in Alcohol Misuse and Alcohol Use Disorder in Women.

Recent evidence indicates that the United States is facing a public health crisis of alcohol misuse and alcohol use disorder (AUD), which has been fueled in part by dramatic rises in binge and heavy drinking and prevalence of AUD in women. Historically, alcohol misuse and AUD have been more prevalent in men than in women. However, recent evidence on data from the past decade shows increases in AUD prevalence rates that are associated with substantially higher binge and heavy drinking and AUD prevalence in women compared to men. This paper first addresses the key roles of stress, trauma, childhood maltreatment, negative affect, and mood and anxiety disorders; sex differences in the presentation of these psychosocial and psychological factors; and their contributions to alcohol misuse, escalation to binge and heavy drinking, and transition to AUD in women. Also examined are potential central and peripheral biological mechanisms by which stressors and traumatic experiences, as well as chronic stress states—including depression and anxiety—may facilitate differential pathways to alcohol misuse, escalation, and transition to AUD in women. Finally, this paper discusses major gaps in the literature on sex differences in these areas as well as the need for greater research on sex-specific pathways to alcohol misuse and transition to AUD, so as to support a more comprehensive understanding of AUD etiology and for the development of new strategies for prevention and treatment of alcohol misuse and AUD in women.

Predictors of alcohol use transitions among drug-using youth presenting to an urban emergency department

BackgroundPrecipitants of alcohol use transitions can differ from generalized risk factors. We extend prior research by predicting transitions in alcohol use disorder (AUD) during adolescence and emerging adulthood.MethodsFrom 12/2009-9/2011, research assistants recruited 599 drug-using youth age 14–24 from Level-1 Emergency Department in Flint, Michigan. Youth were assessed at baseline and four biannual follow-ups, including a MINI Neuropsychiatric interview to diagnose AUD (abuse/dependence). We modeled AUD transitions using continuous time Markov Chains with transition probabilities modulated by validated measures of demographics, anxiety/depression symptoms, cannabis use, peer drinking, parental drinking, and violence exposure. Separate models were fit for underage (<21) and those of legal drinking age.ResultsWe observed 2,024 pairs of consecutive AUD states, including 264 transitions (119 No-AUD→AUD; 145 AUD→No-AUD); 194 (32.4%) individuals were diagnosed with AUD at ≥1 assessment. Among age 14–20, peer drinking increased AUD onset (No-AUD→AUD transition) rates (Hazard ratio—HR = 1.70; 95%CI: [1.13,2.54]), parental drinking lowered AUD remission (AUD→No-AUD transition) rates (HR = 0.53; 95%CI: [0.29,0.97]), and cannabis use severity both hastened AUD onset (HR = 1.18; 95%CI: [1.06,1.32]) and slowed AUD remission (HR = 0.85; 95%CI: [0.76,0.95]). Among age 21–24, anxiety/depression symptoms both increased AUD onset rates (HR = 1.35; 95%CI: [1.13,1.60]) and decreased AUD remission rates (HR = 0.74; 95%CI: [0.63,0.88]). Friend drinking hastened AUD onset (HR = 1.18, 95%CI: [1.05,1.33]), and slowed AUD remission (HR = 0.84; 95%CI: [0.75,0.95]). Community violence exposure slowed AUD remission (HR = 0.69, 95%CI: [0.48,0.99]). In both age groups, males had >2x the AUD onset rate of females, but there were no sex differences in AUD remission rates. Limitations, most notably that this study occurred at a single site, are discussed.ConclusionsSocial influences broadly predicted AUD transitions in both age groups. Transitions among younger youth were predicted by cannabis use, while those among older youth were predicted more by internalizing symptoms and stress exposure (e.g., community violence). Our results suggest age-specific AUD etiology, and contrasts between prevention and treatment strategies.

Genome-wide association studies of the self-rating of effects of ethanol (SRE).

The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N=1527 from 309 families) and European-American (COGA-EA, N=4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA+EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P=3.30E-08 and 11, rs10647170, COGA-AA+EA P=3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P=2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.

Using Machine Learning to Classify Individuals With Alcohol Use Disorder Based on Treatment Seeking Status

ObjectiveThe authors used a decision tree classifier to reduce neuropsychological, behavioral and laboratory measures to a subset of measures that best predicted whether an individual with alcohol use disorder (AUD) seeks treatment. MethodClinical measures (N = 178) from 778 individuals with AUD were used to construct an alternating decision tree (ADT) with 10 measures that best classified individuals as treatment or not treatment-seeking for AUD. ADT's were validated by two methods: using cross-validation and an independent dataset (N = 236). For comparison, two other machine learning techniques were used as well as two linear models. ResultsThe 10 measures in the ADT classifier were drinking behavior, depression and drinking-related psychological problems, as well as substance dependence. With cross-validation, the ADT classified 86% of individuals correctly. The ADT classified 78% of the independent dataset correctly. Only the simple logistic model was similar in accuracy; however, this model needed more than twice as many measures as ADT to classify at comparable accuracy. InterpretationWhile there has been emphasis on understanding differences between those with AUD and controls, it is also important to understand, within those with AUD, the features associated with clinically important outcomes. Since the majority of individuals with AUD do not receive treatment, it is important to understand the clinical features associated with treatment utilization; the ADT reported here correctly classified the majority of individuals with AUD with 10 clinically relevant measures, misclassifying <7% of treatment seekers, while misclassifying 38% of non-treatment seekers. These individual clinically relevant measures can serve, potentially, as separate targets for treatment. FundingFunding for this work was provided by the Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Drug Abuse (NIDA) and the Center for Information Technology (CIT). Research in ContextEvidence Before This Study: Less than 10% of persons who meet lifetime criteria for Alcohol Use Disorder (AUD) receive treatment. As the etiology of AUD represents a complex interaction between neurobiological, social, environmental and psychological factors, low treatment utilization likely stems from barriers on multiple levels. Given this issue, it is important from both a research and clinical standpoint to determine what characteristics are associated with treatment utilization in addition to merely asking individuals if they wish to enter treatment. At the level of clinical research, if there are phenotypic differences between treatment and nontreatment-seekers that directly influence outcomes of early-phase studies, these phenotypic differences are a potential confound in assessing the utility of an experimental treatment for AUD. At the level of clinical practice, distinguishing between treatment- and nontreatment-seekers may help facilitate a targeted treatment approach. Previous efforts to understand the differences between these populations of individuals with AUD leveraged the multidimensional data collected in clinical research settings for AUD that are not well suited to traditional regression methods.Added Value of This Study: Alternating decision trees are well suited to deep-phenotyping data collected in clinical research settings as this approach handles nonparametric, skewed, and missing data whose relationships are nonlinear. This approach has proved to be superior in some cases to conventional clinical methods to solve diagnostic problems in medicine. We used a decision tree classifier to understand treatment- and non-treatment seeking group differences. The decision tree classifier approach chose a subset of factors arranged in an alternating decision tree that best predicts a given outcome. Assuming that the input measures are clinically relevant, the alternating decision tree that is generated has clinical value. Unlike other machine learning approaches, in addition to its predictive value, the nodes in the tree and their arrangement in a hierarchy have clinical utility. With the “if-then” logic of the tree, the clinician can learn what features become important and which recede in importance as the logic of the tree is followed. The decision tree classifier approach reduced 178 characterization measures (both categorical and continuous) in multiple domains to a decision tree comprised of 10 measures that together best classified subjects by treatment seeking status (yes/no).Implications After All the Available Evidence: We leveraged a large data set comprised of 178 clinical measures and using the decision tree approach, we have reduced these to a subset of 10 measures that accurately classified individuals with alcohol dependence by treatment utilization. From this analysis, drinking behavior variables and depression measures are strong treatment seeking predictors. Having identified a cluster of factors that predicts treatment seeking, we can assess the influence of these factors directly on the clinical study outcome measures themselves. In clinical practice these factors can be separate targets for treatment. In clinical research, the group differences my directly influence research outcomes for treatment of AUD.

Sex Differences in Aversion-Resistant Ethanol Intake in Mice.

Compulsive ethanol intake, characterized by persistent consumption despite negative consequences, is an addictive behavior identified by the DSM-5 as a central criterion in diagnosing alcohol use disorders (AUD). Epidemiological data suggest that females transition from recreational alcohol use to AUD more rapidly than males. Because of this potential sex difference in the etiology of AUD, it is critical to assess addictive behaviors such as compulsive intake in both males and females in preclinical studies. We used the model of aversion-resistant ethanol consumption to assess compulsive-like ethanol intake. In these experiments, C57BL6/J mice were first provided with continuous access two-bottle choice between water and ethanol to establish baseline intake. Ethanol solution was then adulterated with increasing concentrations of the bitter tastant quinine hydrochloride. Animals that consume ethanol solution despite its pairing with this negative stimulus are thought to be exhibiting compulsive-like behavior. We found that higher concentrations of quinine were required to suppress ethanol consumption in female mice relative to males. We found no effect of estrous cycle phase on baseline ethanol intake or on quinine-adulterated ethanol intake in females. Collectively, these data suggest that females exhibit a higher degree of aversion-resistance than male mice. Because we observed no effect of estrous cycle phase, it is likely that the presence of threshold levels of estradiol or progesterone, as opposed to their natural fluctuation across the estrous cycle, mediates increased aversion-resistance in females. Alternatively, or in combination, developmental effects of sex hormones could contribute to aversion-resistant ethanol intake.