Towards a molecular epidemiology of alcohol dependence: analysing the interplay of genetic and environmental risk factors.

BACKGROUND: Progress in identifying genetic factors protective against alcohol dependence (AlcD) requires a paradigm shift in psychiatric epidemiology. AIMS: To integrate analysis of research into the genetics of alcoholism. METHOD: Data from prospective questionnaire and interview surveys of the Australian twin panel, and from a subsample who underwent alcohol challenge, were analysed. RESULTS: In men, effects of alcohol dehydrogenase ADH2*1/*2 genotype or high alcohol sensitivity (risk-decreasing), and of history of childhood conduct disorder, or having monozygotic co-twin or twin sister with AlcD (risk-increasing) were significant and comparable in magnitude. Religious affiliation (Anglican versus other) was associated with the ADH2 genotype, but did not explain the associations with AlcD symptoms. No protective effect of the ADH2*1/*2 genotype was observed in women. CONCLUSIONS: The early onset and strong familial aggregation of AlcD, and opportunity for within-family tests of genetic association to avoid confounding effects, make epidemiological family studies of adolescents and young adults and their families a priority.

Genetic differences in alcohol sensitivity and the inheritance of alcoholism risk.

BACKGROUND: Substantial evidence exists for an important genetic contribution to alcohol dependence risk in women and men. It has been suggested that genetically determined differences in alcohol sensitivity may represent one pathway by which an increase in alcohol dependence risk occurs. METHODS: Telephone interview follow-up data were obtained on twins from male, female and unlike-sex twin pairs who had participated in an alcohol challenge study in 1979-81, as well as other pairs from the same Australian twin panel surveyed by mail in 1980-82. RESULTS: At follow-up, alcohol challenge men did not differ from other male twins from the same age cohort on measures of lifetime psychopathology or drinking habits; but alcohol challenge omen were on average heavier drinkers than other women. A composite alcohol sensitivity measure, combining subjective intoxication and increase in body-sway after alcohol challenge in 1979-81, exhibited high heritability (60 %). Parental alcoholism history was weakly associated with decreased alcohol sensitivity in women, but not after adjustment for baseline drinking history, or in men. High alcohol sensitivity in men was associated with substantially reduced alcohol dependence risk (OR = 0.05, 95% CI 0.01-0.39). Furthermore, significantly decreased (i.e. low) alcohol sensitivity was observed in non-alcoholic males whose MZ co-twin had a history of alcohol dependence, compared to other non-alcoholics. These associations remained significant in conservative analyses that controlled for respondents' alcohol consumption levels and alcohol problems in 1979-81. CONCLUSIONS: Men (but not women) at increased genetic risk of alcohol dependence (assessed by MZ co-twin's history of alcohol dependence) exhibited reduced alcohol sensitivity. Associations with parental alcoholism were inconsistent.

Major depressive disorder in a community-based twin sample: are there different genetic and environmental contributions for men and women?

BACKGROUND: Depression affects more women than men and often aggregates in families. Using a community-based sample of twins, we examined the contributions of genetic and environmental factors to the risk of developing major depressive disorder and the effect of sex and different definitions of depression on the relative contributions of genetic and environmental effects. Sex differences in genetic effects were also studied. METHODS: A volunteer sample of Australian twins (2662 pairs) was interviewed using an abbreviated version of the Semi-Structured Assessment for the Genetics of Alcoholism, a semi-structured lay interview designed to assess psychiatric disorders. Depression was defined using 3 different criteria sets: DSM-III-R major depressive disorder, DSM-IV major depressive disorder, and severe DSM-IV major depressive disorder. Genetic and environmental contributions to the liability to develop depression were estimated using genetic model fitting. RESULTS: Lifetime prevalences were 31% in women and 24% in men for DSM-III-R major depressive disorder, 22% in women and 16% in men for DSM-IV major depressive disorder, and 9% in women and 3% in men for severe DSM-IV major depressive disorder. In women, the simplest model to fit the data implicated genetic factors and environmental factors unique to the individual in the development of depression, with heritability estimates ranging from 36% to 44%. In men, depression was only modestly familial, and thus individual environmental factors played a larger role in the development of depression. For DSM-III-R major depressive disorder, there were statistically different estimates for heritability for men vs. women. For both sexes, the relative contributions of genetic and environmental factors were stable using different definitions of depression. CONCLUSIONS: There was moderate familial aggregation of depression in women and this primarily was attributable to genetic factors. In men, there was only modest familial aggregation of depression. For both men and women, individual environmental experiences played a large role in the development of depression. Major depressive disorder as defined by DSM-III-R was more heritable in women as compared with men. The relative contributions of genetic and environmental factors in the development of depression were similar for varying definitions of depression, from a broad definition to a narrow definition.

Potential psychodynamic factors in physician-assisted suicide.

A number of assumptions underlying the debate over physician-assisted suicide (PAS) deserve closer scrutiny. It is often implicitly assumed that decisions as to the competency of the patient to request PAS can be accurately made, and that the treating physician's values and intrapsychic conflicts can be successfully separated from the decision to accede to or reject the patient's request. This article argues that in such an emotionally-laden decision, such factors may play a significant role, and that even were PAS to gain widespread acceptance, ignoring them may lead to errors in classifying patients either as appropriate or inappropriate for PAS.

Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: Alcoholism and substance dependence frequently co-occur. Accordingly, we evaluated the familial transmission of alcohol, marijuana, and cocaine dependence and habitual smoking in the Collaborative Study on the Genetics of Alcoholism. METHODS: Subjects (n=1212) who met criteria for both DSM-III-R alcohol dependence and Feighner definite alcoholism and their siblings (n=2755) were recruited for study. A comparison sample was also recruited (probands, n=217; siblings, n=254). Subjects were interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism. The familial aggregation of drug dependence and habitual smoking in siblings of alcohol-dependent and non-alcohol-dependent probands was measured by means of the Cox proportional hazards model. RESULTS: Rates of alcohol, marijuana, and cocaine dependence and habitual smoking were increased in siblings of alcohol-dependent probands compared with siblings of controls. For siblings of alcohol-dependent probands, 49.3% to 50.1% of brothers and 22.4% to 25.0% of sisters were alcohol dependent (lifetime diagnosis), but this elevated risk was not further increased by comorbid substance dependence in probands. Siblings of marijuana-dependent probands had an elevated risk of developing marijuana dependence (relative risk [RR], 1.78) and siblings of cocaine-dependent probands had an elevated risk of developing cocaine dependence (RR, 1.71). There was a similar finding for habitual smoking (RR, 1.77 in siblings of habitual-smoking probands). CONCLUSIONS: Alcohol, marijuana, and cocaine dependence and habitual smoking are all familial, and there is evidence of both common and specific addictive factors transmitted in families. This specificity suggests independent causative factors in the development of each type of substance dependence.

Suicidal behaviour: an epidemiological and genetic study.

BACKGROUND: Psychiatric history, familial history of suicide attempts, and certain traumatic life events are important predictors of suicidal thoughts and behaviour. We examined the epidemiology and genetics of suicidality (i.e. reporting persistent suicidal thoughts or a plan or suicide attempt) in a large community-based sample of MZ and DZ twin pairs. METHOD: Diagnostic telephone interviews were conducted in 1992-3 with twins from an Australian twin panel first surveyed in 1980-82 (N = 5995 respondents). Data were analysed using logistic regression models, taking into account twin pair zygosity and the history of suicidality in the respondent's co-twin. RESULTS: Lifetime prevalence of suicidal thoughts and attempts was remarkably constant across birth cohorts 1930-1964, and across gender. Major psychiatric correlates were history of major depression, panic disorder, social phobia in women, alcohol dependence and childhood conduct problems. Traumatic events involving assault (childhood sexual abuse, rape or physical assault) or status-loss (job loss, loss of property or home, divorce), and the personality trait neuroticism, were also significantly associated with suicide measures. Prevalence of serious suicide attempts varied as a function of religious affiliation. After controlling for these variables, however, history of suicide attempts or persistent thoughts in the respondent's co-twin remained a powerful predictor in MZ pairs (odds ratio = 3.9), but was not consistently predictive in DZ pairs. Overall, genetic factors accounted for approximately 45% of the variance in suicidal thoughts and behaviour (95% confidence interval 33-51%). CONCLUSIONS: Risk of persistent suicidal thoughts and suicide attempts is determined by a complex interplay of psychiatric history, neuroticism, traumatic life experiences, genetic vulnerability specific for suicidal behaviour and sociocultural risk or protective factors.

Common genetic risk factors for conduct disorder and alcohol dependence.

The association between retrospectively reported childhood conduct disorder (CD) and a history of alcohol dependence (AD) was examined in a sample of 2,682 male, female, and unlike-sex adult twin pairs. There was a strong association between CD and AD in both men (tetrachoric r = .34, odds ratio = 2.8) and women (tetrachoric r = .53, odds ratio = 9.9). Genetic factors accounted for most of the association between CD and AD liability in men and women, with the remainder of the association being due to nonshared individual-specific environmental factors. Genetic influences common to CD and AD accounted for 17% and 35% of the genetic variation in AD liability in men and women, respectively, and accounted for 11% and 23% of the total variation in AD liability in men and women, respectively. The results suggest that there are common genetic risk factors for CD and AD or that CD itself is an important genetically influenced risk factor for AD.

Temporal stability of antisocial personality disorder: blind follow-up study at 8 years.

The study objective was to examine the temporal stability of the antisocial personality disorder (ASPD) diagnosis based on whether specific antisocial symptoms were considered to be related to substance abuse. A total of 407 adults who were initially part of a family study of alcoholism and sociopathy were blindly reassessed an average of 8 years later, using the Home Environment and Lifetime Psychiatric Evaluation Record (HELPER) and basing diagnoses on the clinician's best final estimate using all sources of data. "Narrow" and "broad" ASPD diagnoses were made at both times based on whether individual symptoms were counted toward diagnosis if they occurred in the setting of significant substance abuse. kappa values varied from 0.31 to 0.68, with more restrictive methods of diagnosis being less stable. After deriving estimates of sensitivity and specificity of diagnosis, the probability of being a "case" could be assigned based on the reported number of conduct problems occurring before age 15 as a clinical covariate for diagnosis. We conclude that diagnosing ASPD without attempting to attribute the cause of individual symptoms to substance abuse results in substantially greater temporal stability. Using a broader definition, the diagnosis of ASPD is highly sensitive (P = .97) and specific (q = 0.93). These findings may allow more accurate diagnosis of ASPD in drug-abusing individuals.

Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men.

BACKGROUND: Genetic influences on alcoholism risk are well-documented in men, but uncertain in women. We tested for gender differences in genetic influences on, and risk-factors for, DSM-III-R alcohol dependence (AD). METHOD: Diagnostic follow-up interviews were conducted in 1992-3 by telephone with twins from an Australian twin panel first surveyed in 1980-82 (N = 5889 respondents). Data were analysed using logistic regression models. RESULTS: Significantly higher twin pair concordances were observed in MZ compared to DZ same-sex twin pairs in women and men, even when data were weighted to adjust for over-representation of well-educated respondents, and for selective attrition. AD risk was increased in younger birth cohorts, in Catholic males or women reporting no religious affiliation, in those reporting a history of conduct disorder or major depression and in those with high Neuroticism, Social Non-conformity, Toughmindedness, Novelty-Seeking or (in women only) Extraversion scores; and decreased in 'Other Protestants', weekly church attenders, and university-educated males. Controlling for these variables, however, did not remove the significant association with having an alcoholic MZ co-twin, implying that much of the genetic influence on AD risk remained unexplained. No significant gender difference in the genetic variance in AD was found (64% heritability, 95% confidence interval 32-73%). CONCLUSIONS: Genetic risk-factors play as important a role in determining AD risk in women as in men. With the exception of certain sociocultural variables such as religious affiliation, the same personality, sociodemographic and axis I correlates of alcoholism risk are observed in women and men.

Characteristics of injection drug users derived from a large family study of alcoholism.

Most descriptive studies on injection drug users (IDUs) has used treatment or referral samples. This study uses relatives ascertained through the Collaborative Study on the Genetics of Alcoholism (COGA) to describe patterns of drug use, psychiatric comorbidity, and selected high-risk behaviors among IDUs not ascertained through treatment or other referral networks. Relatives (N = 5,520) of alcoholic probands were administered a semistructured interview, the Semistructured Assessment for the Genetics of Alcoholism (SSAGA), which assesses lifetime psychiatric symptoms and psychoactive substance use. IDUs were compared with these who had never used cannabis more than 20 times or other drugs more than 10 times (minimal drug use group), those who had used cannabis more than 20 times but no other illicit drugs more than 18 times (cannabis users), and those who had used other drugs more than 10 times but who had never injected (other drug users). Compared with other drug users, IDUs reported using more classes of drugs and began drug use at an earlier age. IDUs were significantly more likely to receive diagnoses of antisocial personality disorder (ASPD) and alcohol dependence, and reported elevated rates of suicidal ideas and attempts. IDUs were more likely to report a variety of behavioral difficulties beginning before age 15, and were more likely to engage in high-risk sexual behaviors. Half of the IDUs reported having shared needles; shares were more likely to receive a diagnosis of ASPD, but did not differ on reporting high-risk behaviors. IDUs, regardless of whether selected through treatment, have high lifetime rates of mood disturbance and ASPD, and are likely to have a history of conduct difficulties beginning before age 15 years and to subsequently engage in a variety of other high-risk behaviors.

Nicotine withdrawal in women.

Associations between self-report symptom profiles for nicotine withdrawal, personality (TPQ, EPQ-R), life-time history of psychopathology and smoking history were examined in data obtained from 553 female adult Australian twins (246 regular smokers), aged 32-48 years, who had participated in a telephone interview survey that included life-time assessments of smoking history, nicotine dependence and symptoms of withdrawal. Two hundred and two respondents were from high-risk pairs where either the respondent or the respondent's co-twin had reported a life-time history of alcohol dependence; 351 were from control pairs. Latent class analysis was used to identify subtypes ('classes') of smokers reporting similar withdrawal symptom profiles. Three major classes were identified which appeared to represent a continuum from mild to severe nicotine withdrawal. Smokers from the severe withdrawal class were best characterized by hands shaking and by the prominence of depressive features. There were marked increases in life-time alcohol dependence rates as a function of severity class. In contrast, significantly elevated rates of major depression, conduct disorder and anxiety disorder were observed only among smokers from the most severe withdrawal class. Neuroticism was the only personality factor strongly associated with the development of withdrawal symptoms.

Modeling genetic and environmental influences in the etiology of conduct disorder: a study of 2,682 adult twin pairs.

The etiology of conduct disorder (CD) was examined retrospectively in a sample of 2,682 male, female, and unlike-sex adult twin pairs from the community-based Australian Twin Register. Model-fitting analyses indicated a substantial genetic influence on risk for CD, accounting for 71% of the variance (95% confidence interval [CI] = 32-79%). There was not a statistically significant effect of the shared environment in the best-fitting model of CD, but a modest effect of the shared environment on the risk for CD could not be rejected (95% CI = 0-32%). The magnitude of genetic and environmental influences for CD liability did not vary significantly for boys and girls, and the specific genetic and environmental mechanisms important for the development of CD appeared to be largely the same for both sexes. The fit of a multiple-threshold model raises the possibility that CD may not necessarily be a discrete entity but rather an extreme of the normal variation in conduct-disordered behavior found in the general population.

Psychopathology and HIV risk behaviors among injection drug users in and out of treatment.

To replicate prior descriptions of injection drug users (IDUs), 158 IDUs recruited via a street-outreach program were compared to 320 non-IDUs on measures of substance use, lifetime psychopathology, and HIV risk behavior. IDUs were more likely to receive a diagnosis of antisocial personality disorder, but not other psychiatric diagnoses, and to report dependence on multiple substances. IDUs reported more HIV risk behaviors, but perceived HIV risk did not differ from non-IDUs. Compared to IDUs who declined treatment, IDUs willing to accept treatment did not differ on drug-related problems, lifetime psychopathology, or perceived HIV risk.

Reliability and reporting biases for perceived parental history of alcohol-related problems: agreement between twins and differences between discordant pairs.

OBJECTIVE: Previous research suggests that family history of alcoholism assessments may be biased by characteristics of the informant. In this report, the reliability and potential biases in offspring reports of paternal and maternal alcohol-related problems were examined in a large community sample of adult twins. METHOD: Subjects were volunteer participants in the Australian NH&MRC twin registry. Agreement between twin pairs on reports of paternal and maternal alcohol problems was assessed in 2,657 twin pairs (1,444 female-female pairs, 626 male-male pairs, and 587 female-male pairs). In addition, to detect systematic reporting biases, like-sex twin pairs whose paternal alcohol problems reports disagreed (n = 164) were contrasted on measures of personality, state anxiety and depression, parental rearing, alcoholism, and alcohol use. RESULTS: Twin agreement for parental alcohol-related problems was good, with overall kappas of .66 for paternal and .58 for maternal alcohol problems. When discordant twin pairs were compared, we found that women who reported that their father had alcohol problems were significantly lower on EPQ-R Social Conformity than their twin sister who denied paternal alcohol problems: and there was a trend for men who reported that their father had alcohol problems to be higher in negative perceived parenting from father than their twin brother who denied paternal alcohol problems. Twins discordant for reporting paternal alcohol problems did not, however, differ on the major dimensions of personality, state anxiety and depression, alcoholism, or current alcohol use. CONCLUSIONS: The results of this study bolster our confidence in using the family history method to examine characteristics of offspring of alcoholics versus offspring of nonalcoholics on self-reported measures of personality and psychopathology, but suggest that some caution should be exercised when using this method to examine differences in offspring-reported perceptions of parental rearing practices.

Genetics, antisocial personality, and criminal responsibility.

There is now substantial evidence that heritable biological factors play a role in the genesis of repetitive antisocial behavior. The differing conceptual frameworks of behavioral genetics and the law are described, and the implications that current research in behavioral genetics may have for assigning responsibility for unlawful behavior are discussed.

Combined alfentanil-methohexital anesthesia in electroconvulsive therapy.

Eight patients receiving electroconvulsive therapy (ECT) were anesthetized with alfentanil, 25 mcg/kg, plus 20 mg methohexital, alternating with standard methohexital anesthesia. Combination alfentanil-methohexital anesthesia was associated with a 45% increase in EEG seizure duration. Preliminary evidence suggests that ECT anesthesia using short-acting opiate compounds may prove to be a promising alternative to standard modified ECT, especially for patients with brief seizures.

Is alcohol-related flushing a protective factor for alcoholism in Caucasians?

Although alcohol-related flushing seems to be a genetically influenced protective factor for alcoholism in some Asian groups, little is known about whether this is true for Caucasians. The evidence for alcohol-related flushing as a protective factor for the development of alcoholism was examined in a sample of 5831 Australian twins (2041 men, 3790 women) who were administered a structured psychiatric interview. Twin correlations for self-reported adverse alcohol reactions (e.g., "flushing or blushing" and "feeling very sleepy" after drinking 1 or 2 drinks) were modest, suggesting minimal contribution of genetic factors, but when corrected for reliability of measurement, were consistent with moderate heritabilities. In accord with studies examining Asian samples, we found that individuals who experienced adverse reactions after drinking small amounts of alcohol drank less often and slightly less per drinking occasion than those who did not experience adverse reactions. However, those who experienced adverse reactions were more likely to have symptoms of alcoholism and to report a parental history of alcohol problems. We conclude that self-reported alcohol-related flushing is not a protective factor for alcoholism in Caucasians and may be a risk factor.

Abuse of inhalants: a review.

Inhalants, a chemically heterogeneous group of psychoactive substances found in adhesives, lighter fluids, spray paints, cleaning fluids and typewriter correction fluid, may be used by up to 10% of young people. This article reviews the health effects, epidemiology, risk of other substance use and addiction and psychiatric co-morbidity associated with the practice of inhalant use.

A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA.

Within- and cross-center test-retest studies were conducted to study the reliability of a new, semistructured, comprehensive, polydiagnostic psychiatric interview being used in a multisite genetic linkage study of alcoholism. Findings from both studies indicated that reliability for the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was high for DSM-III-R substance dependence disorders, but less so for substance abuse disorders. Reliability of depression was good in both studies, but mixed for antisocial personality disorder (ASP). Findings are presented in terms of specific substance dependence and abuse diagnoses, as well as for depression and ASP. Criterion-specific reliabilities are examined by type of substance used. Although SSAGA was designed to provide for broad phenotyping of alcoholism, review of its new features suggests its suitability for a variety of family studies, not just those focusing on substance abuse.