Biomedical subjects

Marc A Schuckit

Publications and source records attributed to Marc A Schuckit.

At least 37 records · Page 2Linked to original sources

PubMed2006

Precontemplated and impulsive suicide attempts among individuals with alcohol dependence.

OBJECTIVE: Alcohol dependence confers risk for suicidal behavior. Some suicide attempts are precontemplated, whereas other attempts are impulsive. The purpose of this study was to compare characteristics and correlates of impulsive and precontemplated suicide attempts. METHOD: Data were derived from analysis of The Collaborative Study on the Genetics of Alcoholism (COGA), which is a six-site family pedigree study of individuals in treatment for alcoholism (probands), relatives of probands, and control families. Subjects in the analysis were age 18 years or older with a diagnosis of current alcohol dependence according to the Diagnostic and Statistical Manual, Third Edition, Revised. Individuals reporting a lifetime history of one or more suicide attempts were divided into two strata: suicide attempters with a history of suicidal ideation that persisted for a week or more, conceptualized as attempters showing precontemplation (n=330), and suicide attempters without a history of persistent ideation, conceptualized as impulsive attempters (n=343). These groups were compared with subjects with no history of attempts (nonattempters; n=3115). RESULTS: Precontemplated acts were carried out with greater intent and were more likely to result in medical treatment. Dependence on illicit drugs and history of depression were more likely among attempters showing precontemplation. Impulsive attempts were more likely to be carried out by women and individuals with higher levels of alcohol-related aggression. CONCLUSIONS: Prevention of precontemplated suicide attempts by individuals with alcohol dependence should include a focus on recognition and treatment of depressive syndromes. Alcohol-related aggression was elevated among impulsive suicide attempters. Prevention efforts may include interventions targeting aggression.

Adolescent↗

PubMed2005

Evaluation of a depression-related model of alcohol problems in 430 probands from the San Diego prospective study.

BACKGROUND: Some individuals might use alcohol to help cope with stress and feelings of depression. Studies of such depression or affect-related models have produced divergent results, which might reflect different definitions of affective disturbances, varying emphasis on excluding substance-induced depressions, and different approaches to defining family histories (FH). This paper describes a prospective study that evaluates a model of the role of depressive episodes in the development of alcohol-related problems, while controlling for substance-induced mood disorders. METHODS: Personal interviews were obtained 10 and 15 years after 430 Caucasian subjects entered a study of drinking but not alcohol-dependent 20-year olds. An AMOS Structural Equation Model (SEM) was used to evaluate the development of alcohol problems in the context of the FH of alcoholism and independent (i.e., not substance induced) depressive episodes, personal histories of independent depression, levels of stress, social support, drinking to cope with stress, expectations of the effects of alcohol, and peer drinking. RESULTS: The SEM explained 51% of the variance for the 15-year outcome, and demonstrated good fitness characteristics. The FH of mood disorders (FHdep) predicted depressive episodes through interactions with higher stress and an FH of alcoholism (FHalc), as well as in the context of lower social support. Depressive episodes contributed to the development of alcohol problems both directly and through drinking to cope. CONCLUSIONS: In this model when independent depressive syndromes developed in individuals with a FH of alcoholism, they modestly enhanced the risk for alcohol-related problems, but FHalc did not by itself increase the risk for independent depressions.

Adaptation, Psychological↗

PubMed2005

Long-term stability of alcohol and other substance dependence diagnoses and habitual smoking: an evaluation after 5 years.

CONTEXT: A major criterion to validate diagnoses is stability over time. OBJECTIVE: To examine the stability of several classification systems for lifetime diagnosis of alcohol dependence, to identify characteristics predicting stability of alcoholism, and to study stability of lifetime assessments of habitual smoking (1 pack per day for at least 6 months) and other drug dependence. DESIGN: Participants in the Collaborative Study on the Genetics of Alcoholism were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism and reevaluated 5 years later. Initial and follow-up interviews were available for 1728 individuals (641 index cases, 800 siblings, 287 controls) with lifetime diagnoses of alcohol dependence, other substance dependence (marijuana, cocaine, other stimulants, sedatives, opioids), or habitual smoking at first interview. The likelihood that an individual with a lifetime history of substance dependence or habitual smoking at the first interview retained this classification after 5 years was examined to assess stability of diagnosis. RESULTS: Stability of a lifetime diagnosis of alcohol dependence varied among the subject groups of index cases, siblings, and community-based controls. Alcohol dependence as defined by DSM-III-R criteria was highly stable in the index cases (90.5% women, 94.7% men) but much less stable in the community-based controls (27.5% women, 64.7% men). The most important characteristic associated with stability of diagnosis of alcohol dependence was severity, defined by the number of alcohol-related symptoms. Other DSM-III-R substance dependence disorders varied in the stability of diagnosis over a 5-year period. Lifetime history of habitual smoking was highly stable in all subject groups (96.0% overall). CONCLUSIONS: Stability of lifetime assessment of alcohol dependence varies depending on severity of illness. Severe cases of alcohol dependence are more likely to be stable, whereas general population cases of alcohol dependence are less likely to have stable diagnoses. The stability of diagnosis for other substance dependence varies from substance to substance.

Adolescent↗

PubMed2005

Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse.

CONTEXT: Relapse is a common clinical problem in individuals with substance dependence. Previous studies have implicated a multifactorial process underlying relapse; however, the contribution of specific neural substrates has not yet been examined. OBJECTIVE: To determine whether results from functional magnetic resonance imaging (fMRI) shortly after drug cessation could predict relapse in stimulant-dependent individuals. PARTICIPANTS AND DESIGN: Treatment-seeking methamphetamine-dependent males (N = 46) underwent fMRI 3 to 4 weeks after cessation of drug use. Of the 40 subjects who were followed up a median of 370 days, 18 relapsed and 22 did not. MAIN OUTCOME MEASURE: Blood oxygen level-dependent fMRI activation during a simple 2-choice prediction task. RESULTS: The fMRI activation patterns in right insular, posterior cingulate, and temporal cortex obtained early in recovery correctly predicted 20 of 22 subjects who did not relapse and 17 of 18 subjects who did. A Cox regression analysis revealed that the combination of right middle frontal gyrus, middle temporal gyrus, and posterior cingulate activation best predicted the time to relapse. CONCLUSION: To our knowledge, this is the first investigation to show that fMRI can be used to predict relapse in substance-dependent individuals.

Adult↗

PubMed2005

The level of response to alcohol in daughters of alcoholics and controls.

BACKGROUND: The low level of response (LR) to alcohol is a genetically influenced characteristic related to the development of alcohol use disorders (AUDs). This phenotype is found in men with a family history (FH) of alcoholism, predicts future AUDs, and has heritabilities as high as 60%. However, despite evidence of genetic influences for AUDs in both sexes, the majority of studies evaluating differences in LR across high- and low-risk groups have been conducted on males, and it is unclear how generalizable these results are to women. METHODS: Twenty-five women who are family history positive (FHP) for alcohol dependence were matched with 25 women with no FH of alcoholism (FHN) on factors that may impact LR. Using an alcohol challenge paradigm, data on the reaction to a moderate dose of alcohol were gathered over a period of 3.5 h. Assessments included breath alcohol concentrations (BrACs), the Subjective High Assessment Scale (SHAS), as well as body sway or static ataxia. RESULTS: Family history positives reported lower subjective intoxication than FHNs. In addition, when body sway scores were corrected for skewness, FHPs had significantly lower scores on alcohol-related changes in lateral sway. These differences remained after considering the effects of drinking history and BrAC values. CONCLUSIONS: This study evaluated the LR to alcohol in the largest sample of alcohol challenges in matched FHP and FHN women to date. Overall, the findings are consistent with most data from earlier investigations of smaller sized samples of FHP women. The results suggest that, similar to sons of alcoholics, a low LR to alcohol might also be characteristic of daughters of alcoholics.

Adolescent↗

PubMed2005

Informal mentoring between faculty and medical students.

Mentoring skills are valuable assets for academic medicine faculty, who help shape the professionalism of the next generation of physicians. Mentors are role models who also act as guides for students' personal and professional development over time. Mentors can be instrumental in conveying explicit academic knowledge required to master curriculum content. Importantly, they can enhance implicit knowledge about the "hidden curriculum" of professionalism, ethics, values and the art of medicine not learned from texts. In many cases, mentors also provide emotional support and encouragement. The relationship benefits mentors as well, through greater productivity, career satisfaction, and personal gratification. Maximizing the satisfaction and productivity of such relationships entails self-awareness, focus, mutual respect, and explicit communication about the relationship. In this article, the authors describe the development of optimal mentoring relationships, emphasizing the importance of experience and flexibility in working with beginning to advanced students of different learning styles, genders, and races. Concrete advice for mentor "do's and don'ts"is offered, with case examples illustrating key concepts.

Clinical Competence↗

PubMed2005

An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk.

BACKGROUND: Alcoholism is a complex, genetically influenced disorder the cause of which may be better understood through the study of genetically influenced phenotypes that mediate the risk. One such intermediate phenotype is the low level of response (LR) to alcohol. This project used a case-control approach to search for genes that may contribute to LR. METHODS: Data were available from alcohol challenges at approximately age 20 and regarding the development of alcohol use disorders over the subsequent 20 years for 85 men, including 40 reported in a previous genetic analysis. LR was evaluated using oral consumption of 0.75 ml/kg of alcohol, after which changes in subjective feelings of intoxication and body sway were measured. Alcohol abuse and dependence were diagnosed by DSM-III-R criteria through structured interviews administered to both the participant and an informant (usually the spouse) 10, 15, and 20 years after initial testing. Four polymorphisms were evaluated, including the serotonin transporter HTTLPR promoter ins/del, GABAAalpha6 Pro385Ser, NPY Leu7Pro, and catalase 262C>T. Two of these, HTTLPR and GABAAalpha6 Pro385Ser, had been previously associated with LR and alcoholism in a preliminary study. RESULTS: The HTTLPR L allele was significantly related to both the LR and alcoholism in an allele-dosage (stepwise) manner. Furthermore, the association remained when L alleles were subdivided into recently reported functional subtypes: the lowest LR was associated with genotypes correlated with the highest serotonin transporter expression. The GABAAalpha6 Ser385 allele showed a nonsignificant trend for association to a low LR, as had been previously observed, although the Ser385 allele is uncommon, and only 18 heterozygotes were in the current group. However, the six men with both LL and Pro385/Ser385 genotypes had the lowest LR, and each had developed alcoholism during follow-up. Neither NPY nor catalase was associated with either LR or alcoholic outcomes, although the sample did not have sufficient power for definitive conclusions. CONCLUSIONS: This report strengthens the support for a relationship between the HTTLPR L and GABAAalpha6 Ser385 alleles to low alcohol LR and to alcoholism in a prospectively studied cohort evaluated for LR in young adulthood and before the onset of alcohol dependence.

Adult↗

PubMed2005

Relationship of age of first drink to child behavioral problems and family psychopathology.

BACKGROUND: Studies have implicated a wide variety of variables as being associated with an early age of first drink (AFD). AFD in turn has been associated with a variety of negative outcomes in adolescence and early adulthood. This study is designed to quantify the contributions of these antecedent variables to prediction of AFD; in particular it will carefully examine the involvement of variables in four areas (child characteristics, family demographics, family psychopathology, and child behavior problems). METHODS: Using data from a multicenter study on alcoholism, we first investigated the differences between two groups of children (ages 7 to 17 years), one from families heavily loaded for alcohol dependence and the other from population controls. Second, a multidomain, multistep regression model using child characteristics, family demographics, family psychopathology, and child behavior problems was performed to determine significant contributors to predicted AFD. RESULTS: Five variables initially contributed to the prediction of AFD. These included gender, age at interview, the number of adult sibs with alcohol dependence, being held back a year in school, and conduct scale score. However, the number of conduct symptoms appeared to contain the contributions of gender and being held back a grade in school, and these two variables were subsequent removed from the model. The remaining three variables explained 45% of the model variance; age at interview accounted for 38.3%, conduct scale score accounted for 6.2%, and the number of alcohol-dependent adult sibs accounted for 0.5%. No family history measures of alcohol dependence or antisocial personality disorder were contributory to the prediction model for AFD. CONCLUSIONS: Both the "number of conduct symptoms" and the "number of adult sibs with alcohol dependence" are inversely associated with predicted AFD. The latter variable appears marginally predictive of AFD and suggests a condition in which the child's household, regardless of strength of family history of AD (or antisocial personality disorder), appears conducive to early drinking. Thus, child and environmental factors are stronger predictors of age of first drink than family history.

Adolescent↗

PubMed2005

A cross-generational comparison of alcohol challenges at about age 20 in 40 father-offspring pairs.

BACKGROUND: A low level of response (LR) to alcohol is one of several genetically-influenced phenotypes associated with an elevated risk for heavy drinking and alcoholism. While most studies support the influence of genes for this characteristic, no data to date have addressed how LR established from alcohol challenges performs in similarly aged subjects across generations. METHODS: Between 1978 and 1988, 18-to-25-year-old non-alcohol-dependent Caucasian male drinkers participated in the San Diego Prospective Study alcohol challenges. The paradigms included self-reports of feelings of "High" and "Intoxication," as well as alcohol-related changes in body sway. In recent years, 40 18-to-29-year-old offspring of 25 of these original probands were tested using a similar protocol. RESULTS: Despite the passage of two decades between laboratory sessions across generations, for family history positive (FHP) subjects, significant positive correlations were observed for subjective feelings of intoxication and body sway after alcohol. Parent-offspring correlations were in the predicted direction for subjective feelings for family history negatives (FHNs), but were not significant. Across offspring, LR values were lower for FHPs overall, with significant differences at 60 or 90 min for five items. CONCLUSIONS: The similarities in LR across generations, while not proving heritability, are consistent with prior reports regarding genetic influences in the LR to alcohol. The significant correlations across generations and over two decades support the reliability of the alcohol challenge results.

Adult↗

PubMed2005

Autosomal linkage analysis for the level of response to alcohol.

BACKGROUND: The level of response (LR) to alcohol is a genetically-influenced phenotype related to the alcoholism risk. Usually measured by evaluating psychological and physiological changes that follow the administration of alcohol, the heritability of LR is estimated to be between 0.4 and 0.6, and efforts are being made to find genes related to this phenotype. This paper presents data from a family-based genome with linkage analysis focusing on alcohol challenge determinants of LR. METHODS: The subjects were 18-to-29-year-old sibling pairs with at least one parent who was alcohol-dependent and who had experience with alcohol but were not yet alcohol-dependent themselves. Both members of the sibling pairs were given oral alcohol challenges (0.75-0.90 ml/kg of ethanol for females and males, respectively), with LR established using the Subjective High Assessment Scale (SHAS) and changes in body sway (BS) repeatedly over a 3.5-hr. period. Blood samples from siblings and at least one parent were genotyped using 811 microsatellite markers, with results evaluated using several related variance component approaches as implemented in SOLAR for continuous traits. In addition, association was tested using single nucleotide polymorphisms (SNPs) within the KCNMA1, HTR7 and SLC18A2 genes that may relate to a finding on chromosome 10. RESULTS: Data were generated from 238 sib-pairs representing 365 individuals (41.6% were males) from 165 families. The most consistent results across methods and samples were observed for SHAS on chromosome 10 between 120 and 140 cM (with a maximum LOD score of 2.6 at 122 cM), and a second region of possible interest at 173 cM (LOD = 1.2). Statistical analysis with the KCNMA1, HTR7 and SLC18A2 genes, which lie in the support region of interest revealed no evidence for association after correction for multiple comparisons. CONCLUSIONS: These evaluations from the largest known alcohol challenge-based genetic study to date highlight the potential importance of genes on chromosome 10 as possible contributors to the low LR to alcohol as a risk factor for alcoholism.

Adolescent↗

PubMed2005

Prospective evaluation of the four DSM-IV criteria for alcohol abuse in a large population.

OBJECTIVE: In 1994 DSM-IV presented new criteria for substance abuse as repetitive problems in any one of four areas reflecting social, interpersonal, and legal difficulties. The authors systematically evaluate the performance of each of the four diagnostic criteria for alcohol abuse (problems in role functioning, alcohol use in hazardous situations, alcohol-related legal problems, and social or interpersonal problems) and determine the prognosis associated with a threshold of one versus two or more criterion endorsements. METHOD: Baseline and 5-year follow-up data were analyzed for 2,596 men and women from the Collaborative Study on the Genetics of Alcoholism, including 1,881 individuals with no alcohol-related diagnosis, and 715 with alcohol abuse, after excluding subjects with alcohol dependence. Performance of each criterion was analyzed for the entire group and for the 565 individuals who endorsed only one criterion at baseline. RESULTS: One alcohol abuse criterion was endorsed by 79% of subjects with alcohol abuse, 18.5% endorsed two, and 2.5% endorsed three. Compared with subjects who endorsed no criteria, individuals who reported any of the four diagnostic criteria at baseline had higher rates of alcohol and drug intake and related problems and higher rates of future difficulties. Diagnostic thresholds of one versus two abuse criteria at baseline performed equally well regarding most outcomes, although endorsement of two criteria predicted a higher risk for progression to dependence. The criterion most frequently endorsed--hazardous use--was associated with baseline substance use characteristics and problematic outcomes similar to those for the other criteria. CONCLUSIONS: The four DSM-IV alcohol abuse criteria performed well regarding both cross-sectional characteristics and the prediction of future problems, but no single diagnostic criterion was superior to any other. The similarity of outcomes for subjects with diagnostic thresholds of one versus two or more criteria may favor the continued use of a threshold of one criterion in the diagnosis of alcohol abuse.

Adult↗

PubMed2005

Evaluation of a level of response to alcohol-based structural equation model in adolescents.

OBJECTIVE: A low level of response (LR) to alcohol relates to a family history of alcoholism and predicts future heavier drinking and alcohol-related problems. The current analyses evaluate how LR functions within the context of a Social Information Processing Model, using 238 subjects aged 13 to 19 years from the Collaborative Study on the Genetics of Alcoholism (COGA). METHOD: A structural equation model (SEM) was used to evaluate the relationship among (1) a family history (FH) of alcoholism, (2) the LR to alcohol, (3) expectations as measured by the Alcohol Expectancy Questionnaire and (4) the recent pattern of drinking among parents in the home as predictors of the maximum recent quantity of drinking, the maximum number of drinks ever consumed in 24 hours and the number of alcohol problems in the teenage subjects. RESULTS: When tested in the SEM, LR functioned as a mediator of the relationship between an FH of alcoholism and alcoholic outcome, and expectancy functioned as a partial mediator of the relationship between LR and outcome. Invariance testing revealed that the SEM performed similarly in light and heavy drinkers, the two sexes, and older versus young subjects. Both the measurement model and SEM had good characteristics of fit, and direct paths within the model explained 49% of the variance of outcome. CONCLUSIONS: Consistent with results from the San Diego Prospective Study, when tested in the more heterogeneous COGA population, LR functioned as a mediator of the relationship between the FH and alcoholic outcome. In these adolescents, LR not only had a direct relationship to alcoholic outcome but, in contrast to prior results in adults, also appeared to operate through expectations of the effects of alcohol in predicting heavier drinking and a higher rate of alcohol-related problems among teenagers.

Adolescent↗

PubMed2005

Performance of a self-report measure of the level of response to alcohol in 12- to 13-year-old adolescents.

OBJECTIVE: A low level of response (LR) to alcohol characterizes groups at high risk for alcoholism and predicts future heavier drinking and alcohol-related problems. Because LR might change with increasing age and years of drinking, there is a need to measure this phenotype as early as possible in the drinking career. METHOD: Data were generated from 1,106 12- to 13-year-old subjects in the Avon Longitudinal Study of Parents and Children (ALSPAC). Information about alcohol and other substance use and problems was obtained using a structured interview, and LR from the Self-Rating of the Effects of Alcohol (SRE) questionnaire. RESULTS: Drinking was reported by 80 (7.3% of all subjects) boys and girls. Boys comprised 62.5% of the sample; the mean (SD) age of subjects was 12.9 (0.16) years. Among those 80 drinkers, alcohol had been consumed on an average of 5.4 occasions over the prior 6 months, the average maximum drinks ever imbibed was about 3.3, and 23.8% had any of 26 possible alcohol-related problems. In this group, 36.3% had smoked cigarettes, and 12.5% had used marijuana. The First 5 SRE score among drinkers correlated with the maximum number of drinks consumed at one time at .61 (p < .001), the number of alcohol problems at .25 (p < .01) and the frequency of drinking at .29 (p < .01). When considered along with smoking and marijuana histories, sex and weight, the SRE score contributed significantly to the prediction of maximum drinks per occasion (beta = .60, p < .001) and drinking frequency (beta = .24, p < .05), with a trend (beta = .17, p = .08) for alcohol problems. CONCLUSION: These results support the conclusion that a low LR to alcohol correlates well with the maximum number of drinks consumed even early in the drinking career among individuals for whom acquired tolerance or other factors were unlikely to have explained the relationship.

Adolescent↗

PubMed2005

Correlations among first-degree relatives for responses on the Self-Rating of the Effects of Alcohol Questionnaire in teenagers.

OBJECTIVE: The level of response (LR) to alcohol is an intermediate phenotype related to the alcoholism risk, with a heritability of at least 0.4 as estimated from alcohol challenge experiments. A measure of LR that can be used in adolescence at a time close to the first drinking experience, and that is less expensive than alcohol challenge experiments, is the Self-Rating of the Effects of Alcohol (SRE) Questionnaire. This questionnaire contains questions related to the number of drinks required for up to four different effects early in the drinking career ("first five" score). The familial characteristics of SRE responses have been estimated in adults; however, no study has evaluated familial and potential genetic components of the first five SRE score in adolescents. This article presents data regarding the familial nature of SRE-based scores among a sample of teenagers. METHOD: As part of the Collaborative Study on the Genetics of Alcoholism Phase II (follow-up) Protocol, SRE scores were available on 251 females and 236 males ages 13-19 years. These analyses compare the correlations among father-offspring, mother-offspring, sibling pairs and comparable unrelated individuals. RESULTS: For the 487 subjects, correlations among first-degree relatives ranged from 0.14 to 0.22 and were all significant. Correlations among comparable unrelated pairs ranged from 0.02 to 0.06 and were nonsignificant. When males and females were evaluated separately, the pattern of results, with higher correlations among first-degree relatives than among unrelated individuals, was similar, although, perhaps reflecting fewer subjects, correlations were more variable. CONCLUSIONS: Although not providing a definitive evaluation of heritability, the results are consistent with a potential proportion of the variance related to genes for first five SRE scores of between 0.3 and 0.4. These results parallel previously published data in adults and are similar to heritability estimates for LR on alcohol challenges. The data support the potential use of the first five SRE score in adolescents as a measure of LR in genetic and environmental model-based studies in young populations for whom the evaluation of LR is taking place at a time close to the onset of drinking.

Adolescent↗

PubMed2004

Changes over time in the self-reported level of response to alcohol.

AIMS: A low level of response to alcohol, or the need for a higher number of drinks for an effect, is a risk factor for alcohol use disorders. The response to alcohol is usually measured in young subjects, and changes in this phenomenon over time have rarely been evaluated. Reports that, overall, individuals are likely to become more reactive to alcohol with advancing age led to the current evaluation to determine whether the number of drinks needed for an effect decreased between the teens and age 40 in a group of men. METHODS: Data were available from the 20-year follow-up of 202 men who had originally been chosen at age 20 as nonalcoholic subjects from families at high and low risk for alcoholism. The number of drinks required for effects was determined through the Self-Report of the Effects of Alcohol questionnaire (SRE) regarding their recollection of their intensity of reaction early in their drinking careers, as well as reports regarding the recent (e.g. prior 3 month) response to alcohol at the 15- and 20-year follow-ups. RESULTS: Overall, there was a slight decrease in the drinks required for effects (SRE scores) across the three time points which became significant when recent drinking and depressant medication use were evaluated as covariates. When nonalcoholic or light-drinking subjects were evaluated separately, the decrease in the number of drinks needed for effects was more prominent. Among heavier drinkers, there was an increase in the number of drinks required for effects over time. The findings were generally similar for men with and without alcoholic relatives. CONCLUSIONS: The development of a more intense reaction to alcohol, or the need for fewer drinks for an effect, with advancing age may only be relevant to lighter drinkers. Among heavier drinkers, the finding that a higher number of drinks are required for effects may be relatively stable over time.

Adult↗

PubMed2004

Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.

Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P=.000000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.

Alcoholism↗

PubMed2004

A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence.

Smoking is a highly heritable, addictive disorder that commonly co-occurs with alcohol dependence. The purpose of this study is to perform a genomic screen for habitual smoking and comorbid habitual smoking and alcohol dependence in families from the Collaborative Study on the Genetics of Alcoholism (COGA). Subjects were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) to evaluate alcohol dependence and habitual smoking (smoking one pack per day or more for at least 6 months). Sixty seven multi-generational families with 154 independent sibling pairs affected with habitual smoking were genotyped in a screening sample. Analyses on 79 multi-generational families with 173 independent sibling pairs were repeated in a replication sample. Sibpair analyses were performed using ASPEX. Four chromosomal regions in the screening sample had increased allele sharing among sibling pairs for habitual smoking with a LOD score greater than 1 (chromosomes 5, 9, 11, and 21). The highest LOD score was on chromosome 9 (LOD = 2.02; allele sharing 58.9%). Four chromosomal regions also had modest evidence for linkage to the comorbid phenotype habitual smoking and alcohol dependence (chromosomes 1, 2, 11, 15); and the strongest finding was on chromosome 2 (LOD = 3.30; allele sharing 69.1%). Previously identified areas (chromosomes 1 and 7) implicated in the development of alcohol dependence in this same data set did not provide evidence for linkage to habitual smoking in the screening sample. In the replication data set, there continued to be increased allele sharing near peaks identified in the screening sample on chromosomes 2 and 9, but the results were modest. An area on chromosome 7, approximately 60 cM from a location previously identified in linkage analysis with alcohol dependence, had increased allele sharing for the comorbid habitual smoking and alcohol dependence. These data provide evidence of specific genetic regions involved in the development of habitual smoking and not alcohol dependence. Conversely, genetic regions that influence the development of alcohol dependence do not appear to contribute to the development of habitual smoking. Finally, there is also evidence of an area on chromosome 2 that may reflect a common genetic vulnerability locus to both habitual smoking and alcohol dependence.

Adolescent↗

PubMed2004

EEG alpha variants and alpha power in Hispanic American and white non-Hispanic American young adults with a family history of alcohol dependence.

Results from several studies support associations among variants in electroencephalogram (EEG) alpha voltage, alcohol dependence, ethnic heritage, and a family history of alcohol dependence, although no studies have as yet been conducted in individuals of Hispanic ethnicity. Categorization of EEG, by using spectral analyses, into high-, medium-, and low-voltage alpha, as well as absolute EEG power in alpha and beta frequency ranges, was carried out for Hispanic American (n=108) and white non-Hispanic American (n=269) young adult men and women (age range, 18 to 25 years) who had a family history, but no personal history, of alcohol dependence. Eighteen percent (n=70) of the participants were categorized as having a low-voltage alpha EEG, 16% had high-voltage alpha, and 64% had medium-voltage alpha. In comparison with findings for men, women were found to have higher overall power in the low frequency alpha (7.5-9 Hz) and beta (12-20 Hz, 20-50 Hz) frequency ranges. Hispanic Americans had a lower percentage of individuals in the low-voltage alpha group (9%) and more individuals in the medium-voltage alpha group (73%) compared with findings for white non-Hispanic Americans (low-voltage alpha, 19%; medium-voltage alpha, 62%). Results of the current study confirm the presence of ethnic stratification in EEG alpha variants.

Adolescent↗