Most of the genetic covariation between major depressive and alcohol use disorders is explained by trait measures of negative emotionality and behavioral control.

BACKGROUND: Mental health disorders commonly co-occur, even between conceptually distinct syndromes, such as internalizing and externalizing disorders. The current study investigated whether phenotypic, genetic, and environmental variance in negative emotionality and behavioral control account for the covariation between major depressive disorder (MDD) and alcohol use disorder (AUD). METHOD: A total of 3623 members of a national twin registry were administered structured diagnostic telephone interviews that included assessments of lifetime histories of MDD and AUD, and were mailed self-report personality questionnaires that assessed stress reactivity (SR) and behavioral control (CON). A series of biometric models were fitted to partition the proportion of covariance between MDD and AUD into SR and CON. RESULTS: A statistically significant proportion of the correlation between MDD and AUD was due to variance specific to SR (men = 0.31, women = 0.27) and CON (men = 0.20, women = 0.19). Further, genetic factors explained a large proportion of this correlation (0.63), with unique environmental factors explaining the rest. SR explained a significant proportion of the genetic (0.33) and environmental (0.23) overlap between MDD and AUD. In contrast, variance specific to CON accounted for genetic overlap (0.32), but not environmental overlap (0.004). In total, SR and CON accounted for approximately 70% of the genetic and 20% of the environmental covariation between MDD and AUD. CONCLUSIONS: This is the first study to demonstrate that negative emotionality and behavioral control confer risk for the co-occurrence of MDD and AUD via genetic factors. These findings are consistent with the aims of NIMH's RDoC proposal to elucidate how transdiagnostic risk factors drive psychopathology.

Parental depression and offspring psychopathology: a children of twins study.

BACKGROUND: Associations between parental depression and offspring affective and disruptive disorders are well documented. Few genetically informed studies have explored the processes underlying intergenerational associations. METHOD: A semi-structured interview assessing DSM-III-R psychiatric disorders was administered to twins (n=1296) from the Australian Twin Register (ATR), their spouses (n=1046) and offspring (n=2555). We used the Children of Twins (CoT) design to delineate the extent to which intergenerational associations were consistent with a causal influence or due to genetic confounds. RESULTS: In between-family analyses, parental depression was associated significantly with offspring depression [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.20-1.93] and conduct disorder (CD; HR 2.27, CI 1.31-3.93). Survival analysis indicated that the intergenerational transmission of depression is consistent with a causal (environmental) inference, with a significant intergenerational association in offspring of discordant monozygotic (MZ) twin pairs (HR 1.39, CI 1.00-1.94). Logistic regression analysis suggested that the parental depression-offspring CD association was due to shared genetic liability in the parents and offspring. No intergenerational association was found when comparing the offspring of discordant MZ twins [odds ratio (OR) 1.41, CI 0.63-3.14], but offspring of discordant dizygotic (DZ) twins differed in their rates of CD (OR 2.53, CI 0.95-6.76). All findings remained after controlling for several measured covariates, including history of depression and CD in the twins' spouses. CONCLUSIONS: The mechanisms underlying associations between parental depression and offspring psychopathology seem to differ depending on the outcome. The results are consistent with a causal environmental role of parental depression in offspring depression whereas common genetic factors account for the association of parental depression and offspring CD.

Genome-wide association study of pathological gambling.

BACKGROUND: Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence. METHODS: Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence. RESULTS: No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value=6.63×10(-3)); 5'-adenosine monophosphate-activated protein kinase signalling (P-value=9.57×10(-3)); and apoptosis (P-value=1.75×10(-2)) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status. CONCLUSIONS: The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

Common genetic vulnerability for pathological gambling and alcohol dependence in men.

BACKGROUND: In comparison with alcohol dependence (AD), relatively little is known about the causes of pathological gambling (PG). Given the high rate of comorbidity between PG and AD, knowledge about the causes of AD may be applied to understanding those of PG. METHODS: Subjects were adult male twin pairs from the Vietnam Era Twin Registry. Lifetime histories of PG and AD were assessed by structured psychiatric telephone interview. The validity of a continuum of PG liability was tested to determine whether the causes of subclinical PG, or problem gambling, are quantitatively or qualitatively distinct from those of DSM-III-R PG disorder. Genetic model-fitting methods were used to quantify the extent to which the genetic and environmental risk for PG could be explained by the risk for AD. RESULTS: Tests of the continuity model of PG were all consistent with the hypothesis that subclinical PG and DSM-III-R PG disorder have many, perhaps all, of the same risk factors and thus differ quantitatively rather than qualitatively. Depending on the PG definition, between 12% and 20% of the genetic variation and between 3% and 8% of the nonshared environmental variation in the risk for PG were accounted for by the risk for AD. CONCLUSIONS: Subclinical PG, or problem gambling, may be a milder form of PG, rather than an etiologically distinct syndrome. Risk for AD accounts for a significant but modest proportion of the genetic and environmental risk for subclinical PG and DSM-III-R PG disorder.

Antisocial behavior and alcoholism: a behavioral genetic perspective on comorbidity.

Similar to many domains in the psychopathology literature, overlap and covariation between antisocial behavior (ASB) and alcohol dependence (AD) are oft documented but little understood. Although the relation between ASB and AD is reliably found and of substantial magnitude, it is not possible given the extant research to discriminate among alternative causal models that could give rise to this relation (e.g., ASB-->AD, AD-->ASB, reciprocal causation between ASB and AD, common causes of ASB and AD). In our opinion, true comorbidity among disorders can only be demonstrated and understood in the context of considerable knowledge regarding the disorders' underlying causes (viz., pathology and etiology). In this article, we present a number of behavior genetic models that may be useful for illuminating the causes of comorbidity among two or more disorders, as well as for understanding the etiology of each disorder individually. Using these behavior genetic approaches, psychopathology researchers can directly test alternative models for the comorbidity among disorders, as well as estimate the magnitude of different etiological factors (i.e., genetic and environmental influences) on comorbidity. Although not a panacea and somewhat demanding technically, behavior genetic approaches can shed new light on the comorbidity among disorders.

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.

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.

A twin study of the association between pathological gambling and antisocial personality disorder.

Many individuals with a history of pathological gambling (PG) also have a history of engaging in antisocial behaviors, and this has often been interpreted as a result of the former causing the latter. In a sample of 7,869 men in 4,497 twin pairs from the Vietnam Era Twin Registry, the authors examined (a) the association between PG and antisocial personality disorder (ASPD), (b) the extent to which PG might be differentially associated with childhood conduct disorder (CD) and adult antisocial behavior (AAB), and (c) the contribution of genetic and environmental factors to the association of PG with ASPD, CD, and AAB. PG was significantly associated with all 3 antisocial behavior disorders, and the association of PG with ASPD, CD, and AAB was predominantly explained by genetic factors. The results of this study suggest that the greater-than-chance co-occurrence of PG and antisocial behavior disorders is partially due to their sharing a common genetic vulnerability. The antisocial behavior observed among many individuals with PG probably cannot be interpreted as being simply a consequence of the PG.

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.

The impact of sociodemographics, comorbidity and symptom recency on health-related quality of life in alcoholics.

OBJECTIVE: To obtain estimates of the relationship between alcoholism and health-related quality of life (HRQL) in twin pairs discordant for alcohol dependence. METHOD: In 1995, 1,258 male-male twin pair members of the Vietnam Era Twin Registry (total Registry N = 7.375 pairs) were administered a modified Medical Outcomes Study 36 Item Short Form (SF-36) and the Diagnostic Interview Schedule (DIS) to obtain measures of HRQL and a DSM-III-R criteria lifetime diagnosis of alcohol dependence. Mean within pair differences on eight separate SF-36 subscales were calculated for 436 remitted (no alcohol symptoms in the past 5 years) alcohol-dependent discordant twin pairs and for 194 recent (at least one alcohol symptom in the past 5 years) alcohol-dependent discordant pairs before and after adjustment for covariates. Covariates included lifetime physical illness, lifetime psychiatric disorders, lifetime drug dependence, lifetime nicotine dependence, current marital status, current income and severity. RESULTS: In the unadjusted analysis remitted alcoholic twins compared to their nonalcoholic co-twins reported significantly lower mean scores for six of eight SF-36 subscales. Recent alcoholic twins, compared to their nonalcoholic co-twins, reported significantly lower mean scores for all of the SF-36 subscales. However, after simultaneous adjustment for all covariates, no SF-36 subscale mean, except "vitality" among recent alcoholic twins, was significantly different between alcoholic twins and their nonalcoholic co-twins. CONCLUSIONS: Differences in HRQL between alcoholic and nonalcoholic co-twins is due to covariation from physical and psychiatric problems, drug and nicotine dependence, marital status, income and severity.

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.

The genetics of addiction-a translational perspective.

Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene-environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.

The genetics of antisocial behavior.

Overall, the evidence from over 100 twin and adoption studies of antisocial behavior suggests that genetic factors account for about half of the variation in risk. However, behavioral genetic studies of antisocial behavior still tend to produce far-ranging estimates of heritability, suggesting that there may be important moderators of these genetic risk factors. In this review, the results of some recent behavioral genetic studies of antisocial behavior that focus on the following issues are examined: 1) developmental changes in the heritability of antisocial behaviors, 2) developmental subtypes of antisocial behavior disorders, 3) sex differences in the heritability of antisocial behavior, 4) cohort differences in the heritability of antisocial behavior, and 5) the genetics of antisocial behavior comorbidity.

Personality and the inheritance of smoking behavior: a genetic perspective.

In contrast to the extensive research effort to understand the genetic contribution to alcoholism risk, there has been little research directed at understanding genetic influences on smoking behavior. Data from large twin studies in Scandinavia and Australia are consistent with a major genetic influence on the probability that an individual will become a smoker ("initiation") and will persist in the smoking habit once smoking has started ("persistence"). We use data from the 1988/1989 follow-up survey of the Australian NH&MRC twin panel to determine to what degree personality measures (Tridimensional Personality Questionnaire, Eysenck Personality Questionnaire--Revised) and attitudinal and sociodemographic variables (social and political conservatism, education, religious involvement) might account for genetic or environmental influences on smoking. While we find significant phenotypic associations between these variables and smoking, these are too modest to account for much of the genetic variance. Possible mechanisms by which this genetic variance may arise are discussed.

The influence of religion on alcohol use initiation: evidence for genotype X environment interaction.

We examined the possible role of religious upbringing as a mediator of the shared environmental influences and as a moderator of the genetic influences on the risk of alcohol use initiation in a large population-based sample of Dutch adolescent and young adult twins (1967 twin pairs). There was not a significant association between religious participation and alcohol use initiation among Dutch adolescents and young adults. We also hypothesized that the relative magnitude of the genetic influences on the risk of alcohol use initiation would be greater for those adolescents and young adults who were raised in a less religious environment compared to those adolescents and young adults who were raised in a more religious environment. We indeed found higher heritabilities for females without a religious upbringing compared to females with a religious upbringing. Genetic influences accounted for 40% of the variance in alcohol use initiation in nonreligious females, compared to 0% in religiously raised females. Shared environmental influences accounted for 54% of the variance for nonreligious females and 88% of the variance in religious females. For males, the genetic variance was also higher in the nonreligious group compared to the religious group, but this difference was not statistically significant. Whether or not they were raised religiously, the liability to alcohol use initiation in males was moderately influenced by genetic factors (30%) and substantially influenced by shared environmental factors (60%).

The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins.

Not much is known about the genetic and environmental determinants of various aspects of substance use in adolescents. This study examined whether the inheritance of initiation of tobacco use in adolescents is independent of the inheritance of the number of cigarettes smoked. Alternative multifactorial threshold models were applied to data on tobacco use in 1676 Dutch adolescent twin pairs. The three models that were considered are (i) the single liability dimension model, (ii) the independent liability dimension model, and (iii) the combined model (CM). The results showed that there is not one underlying continuum of liability to smoking. The CM was the best-fitting model. This model postulates that there are separate initiation and quantity dimensions but allows for the possibility that there are some individuals who are so low on the liability to level of consumption that they are not using tobacco. There were no differences between males and females in the magnitude of the genetic and environmental influences on individual differences in smoking initiation and quantity smoked. Smoking initiation was influenced by genetic factors (39%) and shared environmental influences (54%). Once smoking is initiated genetic factors determine to a large extent (86%) the quantity that is smoked.

Genetic and environmental contributions to cannabis dependence in a national young adult twin sample.

BACKGROUND: This paper examines genetic and environmental contributions to risk of cannabis dependence. METHOD: Symptoms of cannabis dependence and measures of social, family and individual risk factors were assessed in a sample of 6265 young adult male and female Australian twins born 1964-1971. RESULTS: Symptoms of cannabis dependence were common: 11.0% of sample (15.1% of men and 7.8% of women) reported two or more symptoms of dependence. Correlates of cannabis dependence included educational attainment, exposure to parental conflict, sexual abuse, major depression, social anxiety and childhood conduct disorder. However, even after control for the effects of these factors, there was evidence of significant genetic effects on risk of cannabis dependence. Standard genetic modelling indicated that 44.7% (95% CI = 15-72.2) of the variance in liability to cannabis dependence could be accounted for by genetic factors, 20.1% (95% CI = 0-43.6) could be attributed to shared environment factors and 35.3% (95% CI = 26.4-45.7) could be attributed to non-shared environmental factors. However, while there was no evidence of significant gender differences in the magnitude of genetic and environmental influences, a model which assumed both genetic and shared environmental influences on risks of cannabis dependence among men and shared environmental but no genetic influences among women provided an equally good fit to the data. CONCLUSIONS: There was consistent evidence that genetic risk factors are important determinants of risk of cannabis dependence among men. However, it remains uncertain whether there are genetic influences on liability to cannabis dependence among women.

The genetics of pathological gambling.

Problem and pathological gambling (PG) occurs in about 5% of Americans. Gambling is associated with substantial psychosocial and psychiatric health problems, and the increasing ease of access to gambling may increase its future prevalence. Therefore, it is important to gain greater insight into the causes of PG. Family studies of PG are consistent with a substantial familial impact on vulnerability to PG. However, family studies cannot distinguish genetic from family environmental influences. By contrast, the study of twin pairs permits the genetic and environmental influences on PG to be estimated. The study of gambling behavior among 3,359 twin pair members of the Vietnam Era Twin Registry suggests that: (1) inherited factors explain a substantial proportion of the variance in the report of symptoms of gambling; (2) there is a single continuum of genetic vulnerability that underlies gambling problems of varying severities; and, (3) the co-occurrence of PG with conduct disorder, antisocial personality disorder, and alcohol abuse/dependence is partially explained by genes that influence both PG and these other psychiatric disorders. Neurophysiological correlates of gambling problems and genetically based differences in neurotransmitter systems may provide biological mechanisms that explain the genetic basis for a predisposition to PG.

Early sexual abuse and lifetime psychopathology: a co-twin-control study.

BACKGROUND: This study was designed to determine lifetime prevalence of psychiatric disorders among twins who reported childhood sexual abuse (CSA), and to compare these rates with those among non-abused co-twins. The contribution of familial and individual-specific factors to reported sexual abuse was also examined. METHOD: Information about lifetime psychopathology and substance use was obtained by structured telephone interviews with 5995 Australian twins. Twins who reported a history of childhood sexual abuse (CSA) were contrasted on lifetime psychopathology with subjects without such a history; in addition, comparisons were made between same-sex twin pairs discordant for CSA. RESULTS: A history of CSA was reported by 5.9% of the women and 2.5% of the men. In the sample as a whole, those reporting CSA were more likely to receive lifetime diagnoses of major depression, conduct disorder, panic disorder and alcoholism, and were more likely to report suicidal ideation and a history of suicide attempt. Abused women, but not men, were also more likely to report social phobia. When comparisons were restricted to non-abused co-twins, no differences in psychopathology were seen. However, rates of major depression, conduct disorder and suicidal ideation were higher if both co-twins were abused than if the respondent alone reported CSA. Model-fitting indicated that shared environmental factors influenced risk for reported CSA in women, but not in men. CONCLUSION: The association between CSA and psychopathology arises at least in part through the influence of shared familial factors on both risk of victimization and risk of psychopathology.