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.

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.

Recent progress in psychiatric genetics-some hope but no hype.

The reputation of the field of psychiatric genetics has recently become tarnished in the view of many human geneticists. Too many linked loci were claimed and withdrawn, too many association studies published and not confirmed and, more recently, too many new and different chromosomal regions have been implicated for the same disorder. Here, we summarize recent trends, focusing on research that moves away from traditional linkage studies. Some promising strategies include psychopharmacogenetics, and consideration of endophenotypes such as neurophysiological and behavioral markers in addition to the clinical diagnosis. Utilization of rapid and automated methods for scoring genetic variants in large-scale association studies followed by multivariate analyses, which include environmental as well as genetic data, will likely fare better than traditional linkage analysis in disentangling the complex genetics of psychiatric disorders. Some notable areas of recent progress include quantification of the genetic complexity of autism, identification of genetic variants protecting individuals from alcoholism, and the description of several polymorphisms likely to be relevant to behavior and psychiatry. The most notable example may be a common variant that affects the transcription rate in the promoter for the serotonin transporter gene that may be relevant for individual differences in the response to common anti-depressants.

Gender differences in the development of substance-related problems: the impact of family history of alcoholism, family history of violence and childhood conduct problems.

OBJECTIVE: This study examined gender differences regarding the relative influence of family history of alcoholism (FHA) and family history of violence (FHV) on reported childhood conduct problems (CCP) and adult problems with alcohol, drugs and violence. METHOD: The participants were 110 men and 103 women with alcohol-related problems recruited within 30 days of enrolling in treatment for substance abuse or dependence. Participants completed self-report measures of pretreatment violence, FHV, CCP, substance use and consequences, and demographics; a semi-structured interview was used to assess FHA. RESULTS: Structural equation modeling (SEM) analyses revealed gender differences with regard to the influence of FHA and FHV as important factors in the development of childhood and adult behavioral problems. For women, the influence of FHA on subsequent childhood conduct problems and adult problems with alcohol was accounted for by FHV. For men, FHA was not directly associated with CCP or adult problems with alcohol and violence, but was associated with adult drug problems. For both men and women, FHV was associated with CCP, and CCP were associated with adult problems with drugs and violence. CONCLUSIONS: Overall, the analyses illustrate the relative importance of FHV as a risk factor in the developmental course leading to problems with drugs and violence among individuals with alcohol-related problems enrolled in treatment for substance abuse or dependence. Further, there was evidence that women may be impacted more than men by family background variables (both FHA and FHV) in terms of the development of adult problems with alcohol, drugs and violence.

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.

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.

Evaluating measures of family history of alcoholism: density versus dichotomy.

AIMS: Studies have used myriad measures of family history of alcoholism (FH) making it difficult to compare them directly. Commonly used FH measures partition samples into the well known positive (FH+) and negative (FH-) dichotomy, although quantitative measures of density potentially provide more information. A standard FH measure would facilitate between-study comparisons. The purpose of this study is to evaluate a quantitative FH measure, called Family History Density (FHD), that has theoretical and practical advantages over currently used measures. DESIGN: Logistic regression equations were estimated for FHD and six commonly used FH measures on alcohol dependence diagnosis, and two measures of alcoholism severity (i.e. withdrawal and tolerance). PARTICIPANTS: Subjects recruited for studies (254 men and 97 women) completed a structured clinical assessment. MEASUREMENTS: Alcoholism diagnosis and endorsement of tolerance or withdrawal symptoms were obtained using the alcohol module from the NIMH Diagnostic Interview Schedule III-R (DIS III-R). Family history of alcoholism was coded using the criteria from the Family Informant Schedule and Criteria (FISC). FINDINGS: All FH measures were associated with alcohol dependence diagnosis, development of tolerance and experiencing withdrawal symptoms in men. In women, only FHD and Parent were significantly associated with all three outcomes. CONCLUSIONS: FHD is a good candidate to be a standard FH measure because it is quantitative, based on familial relatedness and capable of accounting for significant variation in alcoholism diagnosis and two indices of alcoholism severity in men and in women.

Y-chromosome effects on Drosophila geotaxis interact with genetic or cytoplasmic background.

Previously, all of the major fruit fly, Drosophila melanogaster, chromosomes (I, II and III) have been shown to be associated with geotaxis, but the Y chromosome has not. Using two methods (back-crossing and chromosome substitution), Y chromosomes from lines that have evolved stable, extreme expressions of geotaxis were placed into different genetic and cytoplasmic backgrounds to test the resulting males for geotaxis. The results of the back-crossing do not support the interpretation of Y-chromosome effects on geotaxis. These tests do not have sufficient statistical power, however, to detect small genetic effects. In the chromosome substitution experiment, the geotaxis-line Y chromosomes were placed into high- and low-selected lines, Canton-S and Champaign wild-type backgrounds. The results of the chromosome substitution experiment provide evidence for a Y-chromosome effect on geotaxis in selected geotaxis lines, but not in wild-type stock, backgrounds. These results suggest that the Y chromosome has a small effect on geotaxis, whose detection depends on genetic and/or cytoplasmic background. The implications of these results are discussed for behaviour genetic analysis of D. melanogaster and for issues of statistical power in detecting small genetic effects.

Coming to terms with heritability.

The complex mechanisms of heredity are little-appreciated by non-specialists, in some measure, because of misunderstandings that are perpetuated when words used for technical terms have other, more widely understood, folk meanings. When a word has both technical and folk meanings, it is the responsibility of the specialist to avoid promoting confusion by either using extremely cautious and precise language when using the term or, in cases when confusion is inevitable, abandoning the term in favor of one without a widely understood folk meaning. The study of heredity is beset by such confusion, and the term heritability appears to be at the heart of some of the confusion. In this article, I discuss both the technical and folk meanings of heritability and examine the bridge between them. By continuing to use the term heritability, we risk promulgating serious misunderstanding about the workings of heredity, therefore I suggest selectability as an alternative term to avoid such pitfalls.

A gene correlate of geotaxis near Adh (2-50.1) in Drosophila melanogaster.

As part of a long-term study (38+ years) to identify genetic correlates of geotaxis in Drosophila melanogaster, the investigators report the results of allozyme-level analyses of 2 lines derived from hybridizing high- and low-selected lines that have evolved stable, extreme expressions of geotaxis. Allelic variation at Adh was associated with geotactic performance in 1 hybrid-derived line, but not in another, after 66 free-mating generations beyond the F2 generation. A second-chromosome gene correlate of geotaxis may lie within 1 map unit of Adh. Population genetic analyses suggest that there were different selection pressures on the hybrid-derived lines and that the fixation of PGD-A in the high-geotaxis line was probably due to a founder-effect event.

Analyzing correlations of three types in selected lines of Drosophila melanogaster that have evolved stable extreme geotactic performance.

The behavior-genetic analysis of Drosophila melanogaster with geotactic performance as the phenotype is an ideal model system with which to investigate the complex relations between heredity and behavior. As part of a long-term, 38-year study, we report 4 experiments that identify and analyze trait correlations in the selected high- and low-geotaxis lines. We performed F2 correlational analyses and backcrosses to examine 3 types of correlations: (a) genotype-genotype (alcohol dehydrogenase [Adh]-amylase [Amy]), (b) genotype-phenotype (Adh and Amy-geotaxis), and (c) phenotype-phenotype (mate preference-geotaxis). Only the Adh-geotaxis correlation survived meiosis and reappeared in the F2 generation, which indicates a genotype-phenotype correlation, whereas the others did not. The importance of hybrid correlational analysis to the behavior-genetic analysis of a species is discussed.