Risk Factor For Alcohol Dependence Research Articles

Increased Activation of the ACC During a Spatial Working Memory Task in Alcohol‐Dependence Versus Heavy Social Drinking

Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults. During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non-abstinent-dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol-related thoughts and behavior (Obsessive-Compulsive Drinking Scale-OCDS), alcohol use of the last 90 days, and general intelligence. Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol-dependent participants showed a higher task-related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants. Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task-related activation in the dACC was only observed in alcohol-dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self-regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non-alcohol-related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol-related thoughts.

REVIEW: Consilient research approaches in studying gene × environment interactions in alcohol research

This review article discusses the importance of identifying gene-environment interactions for understanding the etiology and course of alcohol use disorders and related conditions. A number of critical challenges are discussed, including the fact that there is no organizing typology for classifying different types of environmental exposures, many key human environmental risk factors for alcohol dependence have no clear equivalents in other species, much of the genetic variance of alcohol dependence in human is not 'alcohol specific', and the potential range of gene-environment interactions that could be considered is so vast that maintaining statistical control of Type 1 errors is a daunting task. Despite these and other challenges, there appears to be a number of promising approaches that could be taken in order to achieve consilience and ecologically valid translation between human alcohol dependence and animal models. Foremost among these is to distinguish environmental exposures that are thought to have enduring effects on alcohol use motivation (and self-regulation) from situational environmental exposures that facilitate the expression of such motivations but do not, by themselves, have enduring effects. In order to enhance consilience, various domains of human approach motivation should be considered so that relevant environmental exposures can be sampled, as well as the appropriate species to study them in (i.e. where such motivations are ecologically relevant). Foremost among these are social environments, which are central to the initiation and escalation of human alcohol consumption. The value of twin studies, human laboratory studies and pharmacogenetic studies is also highlighted.

PW01-236 - Impulsivity and startle habituation as vulnerability markers for alcoholism

BackgroundImpulsivity has been considered as a risk factor for alcohol dependence. Recent research is focusing on paradigms of the startle response (SR), specifically prepulse inhibition (PPI) and startle habituation (SH), as vulnerability markers for alcoholism. It has been demonstrated impairments in the PPI and the SH in offspring of alcoholics. It has also been shown, using personality questionnaires, that faster habituation may be associated with tendency toward impulsivity and behavioral disinhibition. Our goal is to study the correlation between impulsivity laboratory measures and the SR paradigms, in order to see if they could share a common base as endophenotypes for alcoholism.MethodThe subjects were 40 abstinent alcoholic males, aged 18 to 65 years (mean age 44.73) and who had met DSM-IV criteria for Alcohol Dependence, being abstinent for more than a month at the moment they were tested. Participants underwent testing for PPI and habituation of the acoustic startle response. Impulsivity was assessed with three different laboratory measures: Continuous Performance Test (CPT), Stop-Signal Task and Differential Reinforcement for Low-Rate Responding (DRL6). Analyses were performed using SPSS v.10.0.ResultsWe found a significant positive correlation between CPT-tasks and SH (p< 0,01), and Stop-Signal Task-tasks and SH (p< 0,05), but not with DRL6-tasks. No significant correlation was demonstrated between impulsivity measures and PPI.ConclusionsOur findings suggest the existence of a common base between impulsivity and SH as vulnerability markers for alcohol dependence. Further studies are needed to assess if both could share a common genetic origin.

Epidemiology of Alcohol Abuse and Dependence in Rural Chinese Men

Several national and regional epidemiological studies in China have reported increases in the prevalence of alcohol use disorders over the past 3 decades. This cross-sectional study conducted in 2007 identified 11,884 male subjects aged 18 to 60 years using multi-stage randomized cluster sampling methods in 2 rural communities in China and interviewed 9,866 of them. Current and lifetime alcohol use disorders were assessed with a semi-structured diagnostic interview. The age-standardized prevalence of current (lifetime) alcohol abuse and alcohol dependence in Hunan were 1.8% (4.8%) and 4.7% (8.6%) respectively, and those in Henan were 7.6% (11.8%) and 8.7% (10.8%). Higher age (55 to 60) and lower education were risk factors for alcohol dependence in Hunan while middle age (35 to 44), currently married, and higher education and higher income were risk factors in Henan. Alcohol abuse and dependence are no longer uncommon disorders among rural men in China. Unlike most western reports, alcohol dependence shows higher prevalence than abuse. There are significant differences in the prevalence of alcohol use disorders and the socio-demographic profile of affected individuals in the 2 different regions of the country.

DRD1 5′UTR variation, sex and early infant stress influence ethanol consumption in rhesus macaques

The mesolimbic dopamine system plays an important role in mediating a variety of behaviors and is involved in mediating the reinforcing effects of ethanol. Genes encoding dopamine receptor subtypes are thus good candidate loci for understanding the genetic etiologies of susceptibility to alcohol dependence and its antecedent behavioral phenotypes. We tested whether variation in DRD1 influences alcohol consumption in rhesus macaques and whether its influence is mediated by sex and early rearing experience. We genotyped a single nucleotide polymorphism (-111 G/T) in the 5'UTR of DRD1 in 96 subjects raised with their mothers until 6 months of age (n = 43) or in peer-only groups (n = 53). As young adults they underwent a 7-week voluntary ethanol consumption experiment. anova revealed a significant main effect of sex (F(1,95) = 6.3, P = 0.014) and an interaction between genotype, sex and rearing on ethanol consumption (F(7,95) = 4.63, P = 0.0002). Maternally deprived males heterozygous for the T allele consumed significantly more ethanol (P > t <or= 0.0001) than the other subgroups. Maternal deprivation can produce individuals that are anxious and impulsive, both of which are known risk factors for alcohol dependence. Our work demonstrates a potential role for the dopamine D1 receptor gene in modulating alcohol consumption, especially in the context of early environmental stress.

Childhood Risk Factors for Young Adult Substance Dependence Outcome in Offspring from Multiplex Alcohol Dependence Families: A Prospective Study

Age of onset to begin drinking is a known risk factor for alcohol dependence. Factors have been identified that contribute to age of onset to begin regular drinking. These include reduced P300, increased postural sway, and personality variation. A longitudinal study spanning childhood to young adulthood provided the opportunity to determine if these same factors would predict the presence and onset of substance use disorders (SUD). Multiplex families were identified through two or more alcohol-dependent brothers. Offspring from these multiplex or control families (n = 133) were followed annually during childhood. Using childhood predictors previously identified as risk factors for age of onset to begin drinking, SUD outcome by young adulthood was modeled. Familial risk status was a significant predictor of young adult SUD outcome as a main effect and as an interaction with P300 amplitude recorded before the age of 13. In adolescence (age 15), increased postural sway and familial risk predicted the SUD outcome by age 22. Analysis comparing the presence of one or both risk factors showed that those above the median for sway and below the median for P300 amplitude had substantially increased odds of developing SUD (odds ratio = 8.08 [confidence interval = 1.52-42.83]). Our findings indicate that among the factors predicting age of onset to begin regular drinking, P300 predicts SUD outcome across an 11-year span. The present findings provide the longest follow-up to date demonstrating that neurobiological factors in childhood are among the most salient predictors of young adult SUD outcome.

CS06-01 First experience and later risk of alcohol dependence: an epidemiological and genetic approach on a large sample of young adults

Many risk factors for alcohol dependence have been pointed out on the basis of large cohort analyses, including antisocial personality disorder, familial history of substance abuse and initial effect of the first consumption of alcohol, these factors having large overlaps. In addition, a low level of response to first alcohol drink has been reported to increase the risk of future alcohol-dependence. This response to first dinks is a genetically influenced characteristic, but the genes involved remain unknown.The Susceptibility Addiction Gene Environment (SAGE) cohort was designed to assess addictions and psychiatric disorders in a cohort of young adults. All 3.895 college students of the French region “Champagne Ardennes” were eligible. Of them, 3.056 (1.834 males and 1.224 females; mean age 20.42 years, s.d 1.4) were enrolled on their campus during a single day and completed an intake assessment. The final sample was based on 2.730 subjects (70.08%) who fulfilled the inclusion criteria, namely having ever drink at least once in their lifetime. The level of response to alcohol during early consumption was assessed, as well as the DSM criteria for alcohol dependence at the time of interview. DNA was also collected.Our results confirm the strong association between low level of response to alcohol and the risk of dependence. Furthermore, the genotyping of several candidate genes allowed disentangling the potential intermediate factors between the first consumption and the development of later dependence. These findings emphasize the utility of the endophenotype approach in the genetic study of addictive disorders

Between- and Within-Family Association Test of the Dopamine Receptor D2 TaqIA Polymorphism and Alcohol Abuse and Dependence in a General Population Sample of Adults

Dopaminergic dysfunction has been hypothesized to play an important role in the etiology of alcohol-use disorders. A restriction fragment length polymorphism (RFLP) in the 3' untranslated region (3'UTR) of the DRD2 gene affects gene expression and has been implicated as a risk factor for alcohol dependence. This polymorphism (TaqIA) has been reported as positively associated with alcohol-use disorders in case-control samples, but these results have not been replicated in family-based association studies. The mixed results of association between the DRD2 TaqIA polymorphism and alcohol-use disorders may be the result of differences in sample size, phenotype definition, heterogeneity of the samples, and genetic admixture. We conducted tests of association in a sample of 838 adults participating in the National Youth Survey Family Study (NYSFS). We examined whether the DRD2 TaqIA polymorphism was associated with a symptom-count measure of alcohol abuse and dependence derived from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the Craving Withdrawal Model. Tests of association were nonsignificant across each classification system examined. Power calculations suggested that these results were despite the ability to detect an effect size of 1%. This study supports other family-based association tests that have reported no association between the DRD2 TaqIA polymorphism and alcohol abuse and dependence.

Mutation screen of the GAD2 gene and association study of alcoholism in three populations

Synaptic actions of gamma-amino butyric acid (GABA) have been implicated in many facets of ethanol's effects and risk for alcoholism. We examined whether variation in glutamate decarboxylase-2 (GAD2), a gene encoding for a major enzyme in the synthesis of GABA, contributes to risk of alcohol dependence (AD). We screened GAD2 for sequence variants using dHPLC in a population of 96 individuals. Several single nucleotide polymorphisms (SNPs), including four rare non-synonymous polymorphisms, were identified. Thirteen SNPs located in the GAD2 gene were genotyped in a sample of 113 Russian males with AD and 100 Russian male controls. These analyses revealed a modest association between the functional GAD2 -243 A > G SNP (rs2236418) and AD (allele P = 0.038, genotype P = 0.008). An additional sample of 138 Russian males with AD were genotyped for the GAD2 -243 A > G. These analyses supported an association of this polymorphism with AD (combined sample allele P = 0.038, genotype P = 0.0009). We extended these findings to additional populations: a sample of 538 college students assessed using the AUDIT and a sample of European-American (EA) AD subjects (n = 235) and controls (n = 310). Analyses in these populations did not support a role for GAD2 in alcoholism. In summary, the results of an extensive search for an association of GAD2 with AD suggest that variation in GAD2 is not a major risk factor for AD in EAs. The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD.

Association of μ-Opioid Receptor Gene Polymorphism A118G with Alcohol Dependence in a Japanese Population

Ethanol is considered to activate the brain reward system by increasing the release of an endogenous opioid receptor ligand, β-endorphin. The polymorphism A118G in the µ-opioid receptor gene (OPRM1) causes the amino acid change Asn40Asp and has been reported to affect the affinity of the ligand for the receptor. The association of this polymorphism with the vulnerability to alcohol dependence has been studied in many populations, but not yet in Japanese people. In the present study, we compared the frequencies of the polymorphism OPRM1 A118G between patients with alcohol dependence and healthy control subjects living in a Japanese provincial prefecture. We also genotyped a polymorphism, G1510A, in the acetaldehyde dehydrogenase 2 gene (ALDH2), in which the A allele causes poor metabolism of acetaldehyde, a major metabolite of alcohol. Both OPRM1 118G and ALDH2 1510G were significantly associated with alcohol dependence. These results suggest that OPRM1 118G in addition to ALDH2 1510G might be one of the risk factors for alcohol dependence in Japanese people.

Alcohol dependence and depression among heavy drinkers in Canada

This article describes the prevalence of heavy drinking among the Canadian population and the prevalence of alcohol dependence among heavy drinkers aged 18 or older. It also examines the association of depression to alcohol dependence among the latter group and the correlates of depression and alcohol dependence comorbidity. The data are from a national representative sample of the Canadian population in 2000/01. One in five current drinkers aged 18 or older was classified as a regular heavy drinker. This constituted a significant increase of approximately 2% in the prevalence of heavy drinking from 1996/97 to 2000/01 in Canada ( p < 0.001 ). Although men were more likely to be regular heavy drinkers (29.0%) than women (11.1%), male and female heavy drinkers were about equally as likely to be classified as alcohol dependent (11.6% and 11.1%, respectively). While the prevalence of alcohol dependence among men has remained stable, it has decreased by almost 4% among women ( p < 0.05 ). Among persons who have experienced a depressive episode in the year prior to their 2000/01 interview, the prevalence of alcohol dependence was estimated at 32.3% while it was 9.5% for persons without depression. When several indicators believed to be risk factors for alcohol dependence including personal characteristics, psychosocial factors, lifestyle behaviours and physical health were included in the logistic regression models, the marked difference in alcohol dependence among depressed and non-depressed heavy drinkers remained. The former had 3.6 times the odds of being classified as alcohol dependent compared to the latter (CI=2.9, 4.3). When the same personal, psychosocial, lifestyle and physical health measures were used to explain comorbidity of depression and alcohol dependence, perceived stress was the only factor that was consistently associated with comorbidity among both men and women.

The psychosocial work environment and alcohol dependence: a prospective study

Aims: To examine whether a stressful psychosocial work environment predicts alcohol dependence. Methods: Alcohol dependence of participants in the Whitehall II occupational cohort of London based civil servants (1985–88) was...

The Short‐Term Effects and Unintended Long‐Term Consequences of Binge Drinking in College: A 10‐Year Follow‐Up Study

This study addresses binge drinking in college as a risk factor for heavy drinking and alcohol dependence after college. A national probability sample of 1972 college students from the National Longitudinal Surveys of Youth (NLSY79) was interviewed in 1984 and reinterviewed again as adults in 1994. The short‐term effects of binge drinking in college were assessed as well as the extent to which experiences of negative effects in college predicted patterns of alcohol use across the transition from college into postcollege years. As expected, college binge drinkers were comparatively more likely than nonbinge drinkers to experience one or more alcohol‐related problems while in college. In addition, weighted estimates of DSM‐IV‐defined diagnostic criteria in logistic regression models indicated that the binge drinking patterns exhibited during the college years, for some former college students of both genders, posed significant risk factors for alcohol dependence and abuse 10 years after the initial interview, in conjunction with evidence of academic attrition, early departure from college and less favorable labor market outcomes.

Sociodemographic factors associated with comorbid major depressive episodes and alcohol dependence in the general population.

To estimate the 12-month prevalence of alcohol dependence (AD) among subjects with major depressive episodes (MDEs) and the 12-month prevalence of MDEs among those with AD; to investigate the associations between demographic and socioeconomic characteristics and comorbid MDE and AD, based on established theoretical models; and to compare the rates of mental health service use between groups having high and low risk for comorbid conditions. We used data from the 1996-1997 Canadian National Population Health Survey. MDE and AD were measured using the World Health Organization's Composite International Diagnostic Interview Short Form (CIDI-SF). We calculated the 12-month prevalence of MDEs among participants with AD and of AD among those with MDEs. The associations between demographic and socioeconomic characteristics and comorbidity were investigated. Of participants with MDEs, 8.6% had AD; 19.6% of participants with AD reported having at least 1 MDE in the past 12 months. Being young (aged 12 to 24 years); being divorced, separated, or widowed; and having low family income level were positively associated with MDE, AD, and comorbidity. Among participants with comorbid MDE and AD, those who were aged 12 to 24 years were less likely to have used any mental health services in the past 12 months than were others. Young age, single marital status, and low family income may be potential risk factors for comorbid MDE and AD. Although AD is rare in the general population, public health interventions that target the groups identified as at risk may help to prevent MDE, AD, and comorbidity.

The search for genes related to a low-level response to alcohol determined by alcohol challenges.

A low level of response (LR) to alcohol seems to relate to a substantial proportion of the risk for alcoholism and to have significant heritability. This report describes the results of a genome-wide segregation analysis for the first 139 pairs of full siblings by using an alcohol challenge protocol as a direct measure of LR. Subjects from 18 to 29 years old were selected if the original screen indicated they had an alcohol-dependent parent, reported a personal history of drinking but had no evidence of alcohol dependence, and had a full sibling with similar characteristics. Body sway and Subjective High Assessment Scale scores were measured at baseline and at regular intervals after the administration of a measured dose of alcohol. Participants and available parents were genotyped for 811 microsatellite markers, and resulting data were analyzed with a variance component method. Nine chromosome regions with logarithm of the odds ratio (LOD) between 2.2 and 3.2 were identified; several had previously been implicated regarding phenotypes relevant to alcoholism and the LR to alcohol. Several regions identified in the previous linkage study by using a retrospective self-report questionnaire were potentially confirmed by this study. The strongest evidence was on chromosomes 10, 11, and 22. Several chromosomal areas seem to relate to the low LR to alcohol as a risk factor for alcohol dependence.

Impulsiveness as the intermediate link between the dopamine receptor D2 gene and alcohol dependence.

Reinforcement and reward processes have been proposed as being an intermediate link between the risk for alcohol dependence and the gene coding for the dopamine receptor D2 (DRD2). This hypothesis remains open to speculation, and personality traits such as impulsiveness, a core dimension in addictive disorders, should also be taken into account. For instance, recent evidence in rats showed that DRD2 antagonists might increase impulsivity in decreasing the value of delayed rewards. Considering the pro-impulsiveness role of ethanol observed in clinical practice and epidemiological studies, we analysed the Barratt impulsiveness scores in a sample of 92 alcohol-dependent French patients (57 men and 35 women), according to the TaqI A polymorphism of the DRD2 gene. A2/A2 and A1/A2 genotypes were significantly associated with a higher global impulsiveness than A1/A1 genotype (P=0.02 and P=0.03, respectively). We propose that reward-related impulsiveness may constitute a risk factor for alcohol dependence, and that this core temperament could be partly mediated by the DRD2 gene.

Variation in Alcohol Pharmacokinetics as a Risk Factor for Alcohol Dependence

The significant association between alcohol dehydrogenase (ADH)-2 genotype and alcohol-dependence risk, demonstrated in both Asian and non-Asian populations, suggests a link between the metabolism of alcohol (ethanol) and individual differences in susceptibility to dependence. We tested this hypothesis by following up on subjects who took part in the Alcohol Challenge Twin Study conducted in 1979-1981 and comparing the blood and breath alcohol results in that study between subjects who subsequently did or did not meet diagnostic criteria for lifetime alcohol dependence in 1992-1993. Subjects who met DSM-III-R criteria for lifetime alcohol dependence at follow-up had higher blood and breath alcohol values after alcohol challenge than never-dependent subjects. Multivariate analysis showed independent effects of susceptibility to alcohol dependence and smoking status on blood alcohol concentrations, whereas habitual alcohol intake at the time of the initial study had marginally significant effects. The risk of alcohol dependence was 2-fold higher in men and 3-fold higher in women with blood or breath alcohol concentrations in the highest quartile than in the lowest quartile. In view of this association and the known genetic influences on both alcohol pharmacokinetics and alcohol dependence, it is probable that part of the heritability of dependence is mediated by genes (other than the known ADH2 and ADH3 polymorphisms) affecting alcohol metabolism.

Variation in Alcohol Pharmacokinetics as a Risk Factor for Alcohol Dependence

Background: The significant association between alcohol dehydrogenase (ADH)-2 genotype and alcohol-dependence risk, demonstrated in both Asian and non-Asian populations, suggests a link between the metabolism of alcohol (ethanol) and individual differences in susceptibility to dependence. Methods: We tested this hypothesis by following up on subjects who took part in the Alcohol Challenge Twin Study conducted in 1979–1981 and comparing the blood and breath alcohol results in that study between subjects who subsequently did or did not meet diagnostic criteria for lifetime alcohol dependence in 1992–1993. Results: Subjects who met DSM-III-R criteria for lifetime alcohol dependence at follow-up had higher blood and breath alcohol values after alcohol challenge than never-dependent subjects. Multivariate analysis showed independent effects of susceptibility to alcohol dependence and smoking status on blood alcohol concentrations, whereas habitual alcohol intake at the time of the initial study had marginally significant effects. The risk of alcohol dependence was 2-fold higher in men and 3-fold higher in women with blood or breath alcohol concentrations in the highest quartile than in the lowest quartile. Conclusions: In view of this association and the known genetic influences on both alcohol pharmacokinetics and alcohol dependence, it is probable that part of the heritability of dependence is mediated by genes (other than the known ADH2 and ADH3 polymorphisms) affecting alcohol metabolism.

Alcohol addiction

Two abstracts, presented at the British Pharmacological Society conference in July, shed light on alcohol addiction. Alcohol craving can be triggered by environmental stimuli. Barry Everitt and colleagues have been studying this process and have demonstrated that the so-called ‘emotional brain’ or limbic system is involved. Intriguingly, they have identified a dopamine D3 receptor partial agonist that diminishes cue-controlled drug seeking. Another factor in the development of alcohol dependence is binge drinking. Crews and colleagues, studying CNS alterations associated with binge drinking, found that binge drinking resulted in the induction of many genes, including Fos and Ptgs2. Because adolescent drinking is a particular risk factor for alcohol dependence, the importance of age was also evaluated. CNS changes were found to be greater in the younger rats compared with their older relatives. KP

Sweet taste preference as a risk factor for alcohol dependence.

Previous research has found that alcoholics have a greater preference for sweet solutions than comparison subjects. This study tested the hypothesis that preference for sweet solutions is a marker for alcoholism risk. A total of 122 nonalcoholic subjects (59 men) participated. Fifty-eight subjects had a paternal history of alcoholism, and 64 did not. Each subject rated a series of sucrose solutions for intensity of sweetness and degree of preference. Subjects were able to rate accurately the relative intensity of sweetness in the sucrose solutions. Both subjects with and those without a paternal history of alcoholism preferred a 0.42-M sucrose solution, irrespective of gender. This study failed to support the hypothesis that sweet preference is a marker of alcoholism risk. The sweet preference observed previously among alcoholics may be a consequence of chronic alcohol consumption or other factors associated with heavy drinking.