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.

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.

Serotonin transporter promoter polymorphism genotype is associated with behavioral disinhibition and negative affect in children of alcoholics.

BACKGROUND: Serotonergic (5-HT) dysfunction has been implicated in the etiology of both behavioral disinhibition (BD) and negative affect (NA). This work extends our previous finding of relationships between whole blood 5-HT and both BD and NA in pubescent, but not prepubescent, children of alcoholics and continues examination of a hypothesized role of 5-HT dysfunction in alcoholism risk. The long and short (L and S) variants of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) are responsible for differing transcriptional efficiencies in 5-HT uptake. Although associations have been found between the SS 5-HTTLPR genotype and severe alcoholism and neuroticism, recent reports describe relationships between the LL genotype and both low level of response to alcohol and alcoholism diagnosis and a predominance of the LL genotype in early-onset alcoholics. METHODS: This report is from an ongoing prospective study of the development of risk for alcoholism and other problematic outcomes in a sample of families classified by father's alcoholism subtype. This study examines relationships between 5-HTTLPR genotype and both child BD (Child Behavior Checklist Aggressive Behavior) and NA (Child Behavior Checklist Anxious/Depressed) in offspring from 47 families. RESULTS: Results showed significantly higher levels of BD and NA in the 16 children with the LL genotype than the 46 SS or SL children. CONCLUSIONS: Behaviors of undercontrol, which occur at increased rates in children of alcoholics, may be genetically influenced through the regulation of the 5-HT transporter. Due to the small sample size and the preliminary nature of our findings, replication is necessary.

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.

The problem of college drinking: insights from a developmental perspective.

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. John Schulenberg and Jennifer L. Maggs were Organizers. Stephen W. Long was Chair and provided opening remarks. The presentations were: (1) I'm not a drunk, just a college student: Binge drinking during college as a developmental disturbance, by John Schulenberg; (2) Course of alcohol use disorders during college, by Kenneth J. Sher; (3) How do students experience alcohol and its effects? Positive versus negative expectancies and consequences, by Jennifer L. Maggs; and (4) Brief intervention in the context of developmental trends in college drinking, by G. Alan Marlatt. Critique and commentary were provided by Robert A. Zucker.

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.

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.

Serotonergic function, behavioral disinhibition, and negative affect in children of alcoholics: the moderating effects of puberty.

BACKGROUND: Serotonergic (5-HT) dysfunction has been implicated in both behavioral disinhibition and negative affect in adults. Although our group's previous work found decreased whole blood 5-HT in high versus low behavior problem children of alcoholics, some child/adolescent studies report conflicting results, and 5-HT's role in negative affect has been largely unexamined. Age-related developmental factors may play a role in these relationships. METHODS: This report is from an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by father's alcoholism classification. The present study extends previous work and examines relationships between whole blood 5-HT and both child behavioral disinhibition (an aggression index from the Child Behavior Checklist) and negative affect (Child Behavior Checklist Anxious/Depressed scale) in offspring from 47 families (N = 45 boys and 17 girls; mean age = 10.88+/-2.03 yr). RESULTS: The most important finding was that puberty moderated relationships between 5-HT and both behavioral disinhibition and negative affect with a relationship for pubescent children (n = 14, r = -0.54, p = 0.05: r = -0.57,p = 0.04, respectively) but no relationship for prepubescent children (n = 48, r = 0.05, p = 0.75; r = -0.15, p = 0.31, respectively). CONCLUSIONS: The moderating effects of puberty may help clarify inconsistencies in child/adolescent literature. Furthermore, there appears to be a relationship between 5-HT and negative affect which parallels that between 5-HT and behavioral disinhibition. Pubertal status may be an important variable to evaluate as a moderator in relation to the developmental context of the role 5-HT dysfunction may play in various models of behavior related to alcoholism over the early life course.

Intellectual, cognitive, and academic performance among sons of alcoholics, during the early school years: differences related to subtypes of familial alcoholism.

BACKGROUND: Research on intellectual and cognitive functioning of children of alcoholics has been marked by inconsistency, with some studies unable to document deficits. This discrepancy may reflect the substantial heterogeneity found in the alcoholic population and among families of alcoholics. The current study sought to examine the effects of familial alcoholism subtypes on intellectual, cognitive, and academic performance in early school-aged sons of alcoholics. METHODS: Subjects for the present study were 198 elementary-age boys who were participants in the larger MSU-UM Longitudinal Study. Familial alcoholism subtypes were determined based on fathers' alcoholism and antisocial personality disorder diagnoses. Intellectual functioning was measured with the Wechsler Intelligence Scale for Children-Revised (WISC-R); academic achievement was measured with the Wide Range Achievement Test-Revised. In addition, Mazes and Freedom from Distractability factor scores of the WISC-R were used to assess abstract planning and attention abilities. RESULTS: Children of antisocial alcoholics (AALs) displayed the worst IQ and academic achievement compared with children of nonantisocial alcoholics (NAALs) and controls. In addition, children of AALs displayed relatively poorer abstract planning and attention abilities compared with children from control families. Regression analyses revealed that familial alcoholism subtype continued to account for variance in child intellectual ability even when other factors were excluded. CONCLUSIONS: Findings indicate that children from AAL families are most susceptible to relative intellectual, cognitive, and academic deficits. The study further supports the proposition that familial risk characteristics (i.e., paternal alcoholism and antisociality) may serve as effective indicators of family risk for poor intellectual outcome among offspring as early as the elementary school years.

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.

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.

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.

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.

Birth cohort differences in features of antisocial alcoholism among men and women.

BACKGROUND: This study examines the relations between birth cohort, gender, and family history of alcohol problems on alcohol dependence, and on the endorsement of alcohol abuse/dependence symptoms related to antisocial behavior. METHODS: Men (n = 1,365) and women (n = 625) were recruited from the community, hospitals, and other treatment sites and were given a structured diagnostic interview. Data were analyzed by using logistic regression. RESULTS: Age of first regular alcohol use was lower in more recent birth cohorts for both men and women, with those born in the most recent cohort reporting earliest regular use. The decline across cohort was more dramatic in women than in men. For those participants with a diagnosis of alcohol dependence, being born in a more recent cohort was associated with increased risk of dependence onset before age 25. Among those participants with onset of alcohol dependence before age 25 (n(men) = 400; n(women) = 51), being born in a more recent cohort was associated with increased risk of fights while drinking, police involvement, and drunk driving trouble as well as with increased risk for a diagnosis of abuse or dependence on another drug. CONCLUSIONS: These results suggest that the prevalence of antisocial alcoholism may be increasing for both men and women. These data exemplify how societal change may affect expression of underlying vulnerability for traits thought to be genetically influenced.

Heterogeneity of risk aggregation for alcohol problems between early and middle childhood: nesting structure variations.

We examined how family and child risk factors jointly affected stability and change in externalizing behavior over time in a prospective study of eventual alcohol use disorder. Study participants were community-recruited alcoholic and control families, and their initially preschool-aged male and female children (N = 335). Family risk varied as a function of both parental alcoholism (ALC) and antisocial personality disorder (ASPD) and was evaluated for both parents. Child risk was characterized by a set of risky temperament attributes pertaining to high activity, high reactivity, and low attention span. Externalizing behavior was used as the proxy indicator for later alcohol problems. For children in the high family risk group (involving current ALC in both parents or current ALC + ASPD comorbidity or both), child risk when children were 3-5 years old (Wave 1) directly predicted externalizing behavior when children were 6-8 years old (Wave 2), even when Wave 1 child risk was controlled for. In addition, parents' negative interaction with children at Wave 1 mediated the effect of child risky temperament on Wave 2 externalizing behavior. No such pattern was observed in the low family risk group, where only autostability effects were predictive of outcomes at Wave 2. The importance of nesting structure as an ingredient in the epigenesis of risk was discussed. Its particular relevance in understanding the process of risk transmission among offspring from antisocial alcoholic families was emphasized.

Overt behavior problems and serotonergic function in middle childhood among male and female offspring of alcoholic fathers.

A large body of literature indicates that the serotonergic system is involved in behavioral regulation, as evidenced by the inverse relationship between impulsive aggression and serotonergic function found in adult alcoholics and nonalcoholics. However, studies of this relationship among child and adolescent offspring of alcoholics (COAs) have not previously been done. This study examines the potentially parallel relationship between behavioral dysregulation and low serotonergic function in young COAs. The relationship is of potential interest as a phenotypic marker of biological vulnerability to aggressiveness, which itself has been hypothesized to be a risk factor for later antisocial alcoholism. The present work is part of an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by the fathers' alcoholism classification. We examined the relationship between overt behavior problems in middle childhood (mean age = 10.5 +/- 1.7 years) and whole blood serotonin (5-HT) in a subsample of the offspring (N = 32 boys and 12 girls). Using a Child Behavior Checklist (CBCL) index of behavioral undercontrol, we obtained results indicating that high total behavior problem (TBP) children had lower levels of whole blood 5-HT than did low-TBP children (p < 0.01). These results support the hypothesis that there is an inverse relationship between whole blood serotonin levels and behavior problems in young male and female COAs. A father's alcoholism status was not significantly related to his child's 5-HT level, i.e., the child's phenotypic expression of behavioral dysregulation was more reliably connected to serotonergic function than was paternal alcoholism.

Behavioral outcomes among children of alcoholics during the early and middle childhood years: familial subtype variations.

This study examined early behavioral outcomes among young children of alcoholics (COAs) as a function of differences in subtype of paternal alcoholism. Participants were 212 children (106 girls and 106 boys, ages 3 through 8) and both of their biological parents. Families were characterized as antisocial alcoholics, nonantisocial alcoholics, and nonalcoholic controls. There were significant familial subtype group differences on parent report measures of children's total behavior problems, externalizing behavior, and internalizing behavior, and on measures of children's intellectual functioning and academic achievement. In all instances, COAs had poorer functioning than controls. In the behavior problem domain, but not for the domain of intellectual functioning, children from antisocial alcoholic families had greater problems than children from nonantisocial alcoholic families. In addition to the subtype effects, boys had higher levels of behavior problems than girls in all three areas, and older children had more internalizing problems than younger children. Maternal functioning pertaining to lifetime alcohol problem involvement and antisocial behavior also contributed to child subtype differences in internalizing behavior. Results indicate that, even at very early ages, male and female COAs are heterogeneous populations that are distinguishable by way of familial subtype membership, as well as distinguishable from their non-COA peers. Thus, findings underscore the need to consider the heterogeneity of alcoholism when looking at its effects on child development.