Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism.

Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory γ-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two single-nucleotide polymorphisms (SNPs) and haplotypes were more likely to have alcohol dependence symptoms (rs279858, P=0.01; rs279826, P=0.05; haplotype, P=0.02) and higher NEO Personality Inventory-Revised (NEO-PI-R) Impulsiveness scores (rs279858, P=0.016; rs279826, P=0.012; haplotype, P=0.032) with a stronger effect in women (rs279858, P=0.011; rs279826, P=0.002; haplotype, P=0.006), all P-values are corrected for family history and age. A subset of offspring from these families (n=44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r(2)=0.4; P=0.026) and loss (r(2)=0.38; P=0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (P's<0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.

Disaggregating the distal, proximal, and time-varying effects of parent alcoholism on children's internalizing symptoms.

We tested whether children show greater internalizing symptoms when their parents are actively abusing alcohol. In an integrative data analysis, we combined observations over ages 2 through 17 from two longitudinal studies of children of alcoholic parents and matched controls recruited from the community. Using a mixed modeling approach, we tested whether children showed elevated mother- and child-reported internalizing symptoms (a) at the same time that parents showed alcohol-related consequences (time-varying effects), (b) if parents showed greater alcohol-related consequences during the study period (proximal effects), and (c) if parents had a lifetime diagnosis of alcoholism that predated the study period (distal effects). No support for time-varying effects was found; proximal effects of mothers' alcohol-related consequences on child-reported internalizing symptoms were found and distal effects of mother and father alcoholism predicted greater internalizing symptoms among children of alcoholic parents. Implications for the time-embedded relations between parent alcoholism and children's internalizing symptoms are discussed.

Externalizing symptoms among children of alcoholic parents: Entry points for an antisocial pathway to alcoholism.

The authors examined heterogeneity in risk for externalizing symptoms in children of alcoholic parents, as it may inform the search for entry points into an antisocial pathway to alcoholism. That is, they tested whether the number of alcoholic parents in a family, the comorbid subtype of parental alcoholism, and the gender of the child predicted trajectories of externalizing symptoms over the early life course, as assessed in high-risk samples of children of alcoholic parents and matched controls. Through integrative analyses of 2 independent, longitudinal studies, they showed that children with either an antisocial alcoholic parent or 2 alcoholic parents were at greatest risk for externalizing symptoms. Moreover, children with a depressed alcoholic parent did not differ from those with an antisocial alcoholic parent in reported symptoms. These findings were generally consistent across mother, father, and adolescent reports of symptoms; child gender and child age (ages 2 through 17); and the 2 independent studies examined. Multialcoholic and comorbid-alcoholic families may thus convey a genetic susceptibility to dysregulation along with environments that both exacerbate this susceptibility and provide few supports to offset it.

Insomnia, self-medication, and relapse to alcoholism.

OBJECTIVE: This study was an investigation of the frequencies of insomnia and its self-medication with alcohol in a group of alcoholic patients, as well as the relationship of these variables to alcoholic relapse. METHOD: The subjects were 172 men and women receiving treatment for alcohol dependence. They completed a sleep questionnaire, measures of alcohol problem severity and depression severity, and polysomnography after at least 2 weeks of abstinence. RESULTS: On the basis of eight items from the Sleep Disorders Questionnaire, 61% of the subjects were classified as having symptomatic insomnia during the 6 months before treatment entry. Compared to patients without insomnia, patients with insomnia were more likely to report frequent alcohol use for sleep (55% versus 28%), had significantly worse polysomnographic measures of sleep continuity, and had more severe alcohol dependence and depression. Among 74 alcoholics who were followed a mean of 5 months after treatment, 60% with baseline insomnia versus 30% without baseline insomnia relapsed to any use of alcohol, a significant difference. Insomnia remained a robust predictor of relapse after application of logistic regression analysis to control for other variables. A history of self-medicating insomnia with alcohol did not significantly predict subsequent relapse. CONCLUSIONS: The majority of alcoholic patients entering treatment reported insomnia symptoms. Given the potential link between insomnia and relapse, routine questions about sleep in clinical and research settings are warranted.

Early intervention in the path to alcohol problems through conduct problems: treatment involvement and child behavior change.

A program for the prevention of conduct problems among preschool-age sons of alcoholic fathers was implemented to interrupt what is likely to be a major mediating factor in the development of alcoholism in later years. A population-based sample of 42 families participated in a 10-month intervention involving parent training and marital problem solving. Differences in treatment outcome were examined, with the expectation that level of treatment involvement--entailing both level of participation and level of investment--would account for variability in child outcome at termination. Significant changes in positive and negative child behaviors were observed only within the group of families who completed the program and where the mothers demonstrated a higher level of treatment investment. When pretreatment child, parent, and family predictors of child behavior change were accounted for, subsequent analyses identified maternal treatment investment as a significant predictor of child outcome.

Articulating subtype differences in self and relational experience among alcoholic men using structural analysis of social behavior.

L. Benjamin's (1984) structural analysis of social behavior (SASB) system was used as the organizing framework within which to characterize the phenomenology of self and other relationship experience among subtypes of alcoholic men. Within the context of a community-based study of psychopathology, groups of antisocial alcoholic (AAL), nonantisocial alcoholic (NAAL), and nonalcoholic (control) men completed ratings of their introject (self-concept) and spousal experience. Group differences in demography and psychopathology provided strong support for subtype variations among alcoholic men that could not be attributed to global differences in adaptive functioning. SASB data showed consistency in circumplex ordering across the groups in ratings of self-experience and in ratings of the spousal relationship. AAL men were the most self-neglecting, blaming, and least trusting, and control men were the most relationally connected, with NAAL men falling in between. Despite the importance of the subtyping distinction, in some areas, alcoholism, regardless of subtype, was the core differentiating factor.

Sociopathy, gender, and treatment outcome among outpatient substance abusers.

Antisocial personality disorder (ASPD) may predict poor prognosis but gender/sociopathy relationships to prognosis remain unclear. This study investigated the effects of ASPD upon psychiatric and substance-related outcomes among 235 addiction treatment center outpatients. Prevalence rates for ASPD were similar for males (16%) and females (22%). At baseline, women and ASPD patients displayed greater substance-related and psychiatric severity. At 6-month follow-up, ASPD patients had greater severity on both measures than did patients without ASPD, but women now had equivalent psychiatric severity to men. After controlling for initial severity, ASPD was related to worse substance-related outcomes, but not to worse psychiatric outcomes.

The role of family influences in development and risk.

Various influences in the family environment contribute to children of alcoholics' (COAs') risk of developing alcoholism and other mental health problems. These risk factors include alcohol-specific influences, which selectively predict alcohol problems, and alcohol-nonspecific influences, which predict a variety of mental health problems. Alcohol-specific family influences include modeling of parental drinking behavior, development of alcohol expectancies, and the family's ethnic background. Parental psychopathology, the family's socioeconomic status, and general family psychopathology are examples of alcohol-nonspecific risk factors, which increase the COA's risk of behavior disorders as well as of alcoholism. The families of COA's who are at highest risk for alcoholism and other mental health problems are characterized by the aggregation of numerous alcohol-specific and alcohol-nonspecific risk factors.

Early family-based intervention in the path to alcohol problems: rationale and relationship between treatment process characteristics and child and parenting outcomes.

OBJECTIVE: Risk for subsequent development of alcohol problems is not uniform across the population of alcoholic families, but varies with parental comorbidity and family history. Recent studies have also identified disruptive child behavior problems in the preschool years as predictive of alcoholism in adulthood. Given the quality of risk structure in highest risk families, prevention programming is more appropriately family based rather than individual. METHOD: A family-based intervention program for the prevention of conduct problems among preschool-age sons of alcoholic fathers was implemented to change this potential mediating risk structure. A population-based recruitment strategy enrolled 52 alcoholic families in a 10-month intervention involving parent training and marital problem solving. The study examined the interplay between parent treatment investment and parent and therapist expectations and satisfaction in predicting change in child behavior and authoritative parenting style during the program, and for 6 months afterward among the 29 families whose sustained involvement allowed these effects to be evaluated. RESULTS: Parent expectations at pretreatment influenced their early investment in the program, which in turn predicted child and parenting outcomes. Parent and therapist satisfaction ratings during treatment were associated with one another and with expectations that the program would continue to promote changes in their child. Parent investment was a particularly salient influence on outcome, as higher investment throughout the program was associated with improvement in child behavior and authoritative parenting at termination. CONCLUSIONS: Findings indicate that treatment process characteristics mediate the influence of baseline parent functioning on treatment success and that treatment changes themselves predict later child outcomes.

Preventing alcohol misuse: the impact of refusal skills and norms.

The purpose of this study was to determine the extent to which refusal skills and norm setting mediated the impact of a school-based prevention program from the Alcohol Misuse Prevention Study (AMPS) on adolescent alcohol overindulgence. The AMPS is a randomized, pre-post, experimental-control study. Respondents in the present study included 6th through 10th graders (ns ranged from 232 to 371). Structural equation modeling analyses using EQS indicated that norm setting mediated the effect of the intervention on alcohol overindulgence at the 7th through the 8th grade and at the 8th through the 10th grade. In contrast, although the prevention program served to increase refusal skills, refusal skills did not mediate the effect of the program on alcohol misuse.

National study of the demography of adolescent drinking practices in 1980.

According to a national survey, adolescent drinking patterns appear to have remained relatively stable in the last half decade. Among those aged 16-18, 73% are drinkers; drinking and drunkenness continue to be age- and sex-graded phenomena.

Gender differences in the relationships among SES, family history of alcohol disorders and alcohol dependence.

OBJECTIVE: Potential moderator and mediator roles of several measures of socioeconomic status (SES) were investigated for the relationship between a family history of alcoholism (FH) and alcohol dependence symptoms in adulthood. METHOD: These analyses were performed with a sample of 931 men and 385 women participating in studies at the Alcohol Research Center, University of Michigan. Hierarchical multiple regression equations were used to assess whether SES mediated and moderated relationships between FH and alcohol dependence symptoms. RESULTS: In general, measures of SES (education, occupation, personal and household income) were more important predictors of alcohol dependence symptoms among men, while FH was a stronger predictor among women. In the female sample, measures of personal and household income interacted with family history such that the influence of family history on adult alcohol dependence symptoms was significantly stronger among low income women. Measures of SES and FH were additively related to alcohol dependence symptoms among men. Education partially meditated the relationship between family history and alcohol dependence symptoms among men, indicating that the influence of family history on subsequent alcohol problems among men may be partially due to familial alcoholism's negative effect on educational attainment. CONCLUSIONS: The results of this study suggest the influence of FH on alcohol dependence varies according to SES and gender, and point to the usefulness of examining potential moderators and mediators of family history of alcohol use disorders.

Potential associations among genetic markers in the serotonergic system and the antisocial alcoholism subtype.

Alcoholism is transmitted in families. The complexity and heterogeneity of this disorder has made it difficult to identify specific genetic correlates. One design with the potential to do so is the family-based association study, in which the frequencies of genetic polymorphisms are compared between affected and nonaffected members. Reduced central serotonin neurotransmission is associated with features of an antisocial subtype of alcoholism, although a primary deficit has not been traced to a particular component. Genetic markers related to the sertonergic system have been identified, located, and cloned. If associations can be discovered, the development process for pharmacotherapy could be facilitated. In this review, the evidence for the involvement of the serotonergic system in antisocial alcoholism is examined, and the potential for family-based association studies to identify specific components that may be involved is discussed.

Parental response to competence and trauma in infants with reproductive casualty.

This study of 31 infants in neonatal intensive care and their parents examined the relationship involving infant characteristics (medical and behavioral), parent characteristics (personality and stuational variables), and the development of parental attachment. As expected, infants who were more visually competent had mothers who were more attentive. Contrary to expectation, greater prematurity was related to greater parental involvement. There were important differences in maternal and paternal responses, with mothers using more denial to cope with the medical crisis. Parents who relied heavily on denial were found to have impaired attachment.

Relating early child adjustment to infant and parent temperament.

The central question at issue was the role of both infant and parent temperament in determining child adjustment at age 4. Within the conceptual framework of the New York Longitudinal Study (NYLS), both infant and parent temperament were assessed. Factor analyses yielded three comparable infant and parent temperament factors: Mood, Energy, and Consistency. Correlations with teacher ratings of child adjustment indicated the most significant relationship to be with the infant girls' Mood factor (comparable to the NYLS high-risk "difficult" infant factor). No infant factors were found to relate to boys' adjustment, while maternal Mood was significant across sexes. Indices of the temperamental similarity within families also revealed sex differences relative to adjustment, with similarity across all family members significantly related to adjustment for girls and boy-father dissimilarity significant for boys. Discussion centered around continuity-discontinuity issues relevant to sex differences.

Parental alcoholism and co-occurring antisocial behavior: prospective relationships to externalizing behavior problems in their young sons.

The hypothesis that parental alcoholism and co-occurring antisocial behavior would be indirectly linked to child externalizing behavior problems through child lack of control, current levels of parent depression, family conflict, and parent-child conflict was tested using manifest variable regression analysis. Participants were a community sample of 125 families with an alcoholic father and 83 ecologically matched but nonsubstance abusing families involved in the first 2 waves of an ongoing longitudinal study (with 3 years between each wave). All families had a biological son who was 3-5 years old at study onset. Results revealed that child lack of control mediated the relation between paternal alcoholism and the son's subsequent externalizing behavior problems. Family conflict was a significant mediator of maternal and paternal lifetime antisocial behavior effects and father-son conflict mediated paternal lifetime antisocial behavior effects. Study implications are discussed within the context of parental socialization of antisocial behavior.

Some sociopsychological factors in attempted suicide among urban black males.

This study tests three hypotheses relating to suicidal behavior among urban black males: that black consciousness and group cohesiveness will be lower and depression will be higher. Inner-city, young adult black males with a suicide attempt in the last 6 months, and matched controls were examined. Hypothesis was one supported; the other two received partial support. The validity of the theory of black self-hatred as the basic cause of suicidal behavior among blacks is questioned. Atwo-factor theory of suicide, focusing on forces moving the person away from suicide toward positive subgroup ties, is proposed.

Parent-child interactions in alcoholic and nonalcoholic families.

A community-recruited sample of alcoholic and nonalcoholic families was videotaped in a standardized play task involving parents and their preschool-aged sons. Microanalyses revealed that alcoholic families had lower dyadic synchrony, that parents were viewed as less able to engage their children, and that the coders liked the control parents and children more. Variations in the parent-child interactions are discussed.

Time spent with child and parental agreement about preschool children's behavior.

Although there is a common core of agreement in parental perceptions of their preschool-age sons' problem behavior, perceptions of 107 parents became more concordant as fathers increased the amount of time they spent with their sons. At least within the context of a sample who were at risk for developing abuse of alcohol or other substances and antisocial behavior, fathers who spent less time with their sons perceived them to be less troubled than mothers perceived them to be.

Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems.

Genetic variants in GABRA2 have previously been shown to be associated with alcohol measures, electroencephalography (EEG) ß waves and impulsiveness-related traits. Impulsiveness is a behavioral risk factor for alcohol and other substance abuse. Here, we tested association between 11 variants in GABRA2 with NEO-impulsiveness and problem drinking. Our sample of 295 unrelated adult subjects was from a community of families with at least one male with DSM-IV alcohol use diagnosis, and from a socioeconomically comparable control group. Ten GABRA2 SNPs (single-nucleotide polymorphisms) were associated with the NEO-impulsiveness (P < 0.03). The alleles associated with higher impulsiveness correspond to the minor alleles identified in previous alcohol dependence studies. All ten SNPs are in linkage disequilibrium (LD) with each other and represent one effect on impulsiveness. Four SNPs and the corresponding haplotype from intron 3 to intron 4 were also associated with Lifetime Alcohol Problems Score (LAPS, P < 0.03) (not corrected for multiple testing). Impulsiveness partially mediates (22.6% average) this relation between GABRA2 and LAPS. Our results suggest that GABRA2 variation in the region between introns 3 and 4 is associated with impulsiveness and this effect partially influences the development of alcohol problems, but a direct effect of GABRA2 on problem drinking remains. A potential functional SNP rs279827, located next to a splice site, is located in the most significant region for both impulsiveness and LAPS. The high degree of LD among nine of these SNPs and the conditional analyses we have performed suggest that all variants represent one signal.