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.

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.

Single nucleotide polymorphisms in the REG-CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample.

Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans (NA) experience some of the highest rates of substance abuse of all the US ethnic groups. The described analyses used data from a low-coverage whole genome sequence scan to conduct a genome-wide association study (GWAS) of an impulsivity phenotype in an American Indian community sample (n = 658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using emmax. Simulations were conducted to calculate empirical P-values. Genome-wide significant findings were observed for a variant 50-kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal-specific catenin, in the REG gene cluster. A meta-analysis of GWAS had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of nei endonuclease VIII-like 3 (NEIL3) on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population.

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.

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.

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.

An integrative approach for studying the etiology of alcoholism and other addictions.

Studies of alcoholism etiology often focus on genetic or psychosocial approaches, but not both. Greater understanding of the etiology of alcohol, tobacco and other addictions will come from integration of these research traditions. A research approach is outlined to test three models for the etiology of addictions--behavioral undercontrol, pharmacologic vulnerability, negative affect regulation--addressing key questions including (i) mediators of genetic effects, (ii) genotype-environment correlation effects, (iii) genotype x environment interaction effects, (iv) the developmental unfolding of genetic and environmental effects, (v) subtyping including identification of distinct trajectories of substance involvement, (vi) identification of individual genes that contribute to risk, and (vii) the consequences of excessive use. By using coordinated research designs, including prospective assessment of adolescent twins and their siblings and parents; of adult substance dependent and control twins and their MZ and DZ cotwins, the spouses of these pairs, and their adolescent offspring; and of regular families; by selecting for gene-mapping approaches sibships screened for extreme concordance or discordance on quantitative indices of substance use; and by using experimental (drug challenge) as well as survey approaches, a number of key questions concerning addiction etiology can be addressed. We discuss complementary strengths and weaknesses of different sampling strategies, as well as methods to implement such an integrated approach illustrated for the study of alcoholism etiology. A coordinated program of twin and family studies will allow a comprehensive dissection of the interplay of genetic and environmental risk-factors in the etiology of alcoholism and other addictions.

Predictors of non-response to a questionnaire survey of a volunteer twin panel: findings from the Australian 1989 twin cohort.

Questionnaire surveys, while more economical, typically achieve poorer response rates than interview surveys. We used data from a national volunteer cohort of young adult twins, who were scheduled for assessment by questionnaire in 1989 and by interview in 1996-2000, to identify predictors of questionnaire non-response. Out of a total of 8536 twins, 5058 completed the questionnaire survey (59% response rate), and 6255 completed a telephone interview survey conducted a decade later (73% response rate). Multinomial logit models were fitted to the interview data to identify socioeconomic, psychiatric and health behavior correlates of non-response in the earlier questionnaire survey. Male gender, education below University level, and being a dizygotic rather than monozygotic twin, all predicted reduced likelihood of participating in the questionnaire survey. Associations between questionnaire response status and psychiatric history and health behavior variables were modest, with history of alcohol dependence and childhood conduct disorder predicting decreased probability of returning a questionnaire, and history of smoking and heavy drinking more weakly associated with non-response. Body-mass index showed no association with questionnaire non-response. Despite a poor response rate to the self-report questionnaire survey, we found only limited sampling biases for most variables. While not appropriate for studies where socioeconomic variables are critical, it appears that survey by questionnaire, with questionnaire administration by telephone to non-responders, will represent a viable strategy for gene-mapping studies requiring that large numbers of relatives be screened.

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.

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.

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 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.

Childhood sexual abuse and pathogenic parenting in the childhood recollections of adult twin pairs.

BACKGROUND: We examined the relationship between childhood sexual abuse (CSA), and interviewees' recollections of pathogenic parenting, testing for possible retrospective biases in the recollections of those who have experienced CSA. METHODS: Information about CSA, parental divorce and interviewees' recollections of parental rejection, parental overprotection and perceived autonomy (as assessed through a shortened version of the Parental Bonding Instrument) was obtained through telephone interviews with 3626 Australian twins who had also returned self-report questionnaires several years earlier. Recollections of parental behaviours were compared for individuals from pairs in which neither twin, at least one twin, or both twins reported CSA. RESULTS: Significant associations were noted between CSA and paternal alcoholism and between CSA and recollections of parental rejection. For women, individuals from CSA-discordant pairs reported levels of parental rejection that were significantly higher than those obtained from CSA-negative pairs. The levels of parental rejection observed for twins from CSA-discordant pairs did not differ significantly from those obtained from CSA-concordant pairs, regardless of respondent's abuse status. For men from CSA-discordant pairs, respondents reporting CSA displayed a tendency to report higher levels of parental rejection than did respondents not reporting CSA. Other measures of parenting behaviour (perceived autonomy and parental overprotection) failed to show a clear relationship with CSA. CONCLUSIONS: The relationship between CSA and respondents' recollections of parental rejection is not due solely to retrospective bias on the part of abused individuals and, consistent with other studies, may reflect a pathological family environment with serious consequences for all siblings.

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.

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.

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.

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.

Personality and substance use disorders: II. Alcoholism versus drug use disorders.

The relationship between personality and substance use disorders was investigated in a community-based sample of 638 individuals who were alcoholic and/or had a drug use disorder, and 1,530 individuals who did not have a substance use disorder. Personality was assessed by the Multidimensional Personality Questionnaire; substance use diagnoses were based on standard criteria as assessed by interview. Data were analyzed using a 3-factor (Gender x Alcoholism x Drug Use Disorder) multivariate analysis of variance. The significant alcoholism main effect was associated primarily with negative emotionality, whereas the significant drug use disorder main effect was associated primarily with constraint. No significant interactions with gender were observed. These findings suggest that the elevated levels of behavioral disinhibition observed with alcoholic individuals may be attributable to a subset of alcoholic individuals who also abuse drugs other than alcohol.

The heritability of alcoholism symptoms: "indicators of genetic and environmental influence in alcohol-dependent individuals" revisited.

There is consistent evidence from twin and adoption studies implicating genetic factors in the etiology of alcoholism, yet few studies have examined the role of genetic influences on individual symptoms of alcoholism. In a previous study of 113 male twins, Johnson et al. (1996a) identified 7 alcoholism symptoms that were more "genetic" and 14 that were more "environmental" (that is, non-genetic) in their etiology by examining symptom concordances among monozygotic and dizygotic twin pairs. The present study represents an attempt to replicate the results of this previous study and extend them by estimating the contribution of genetic factors to the variation in liability for different alcoholism symptoms. Subjects were 3356 male twin pairs from the Vietnam Era Twin Registry. Lifetime histories of alcoholism symptoms were assessed by a structured psychiatric telephone interview. The results of the previous study were not replicated. The correlations between symptom classifications as genetic and non-genetic in the present and previous study were nonsignificant and ranged from -0.27 to 0.11. However, within the present study the correlation between symptom classifications as genetic and non-genetic was statistically significant across random split-half subsamples (r = 0.59); nine alcoholism symptoms were consistently classified as genetic and six symptoms as non-genetic in their etiology. Model-fitting analyses applied to different alcoholism symptoms yielded heritability estimates ranging from 0.03 to 0.53 with broad and overlapping confidence intervals around these estimates, ranging from 0.00 to 0.65. The results of this study highlight the difficulty of identifying more or less heritable phenotypes in twin research, and suggest that it may not be possible to identify specific alcoholism symptoms that are more genetic in their etiology than others. Nevertheless, there appears to be potentially important variation in the relative magnitude of genetic influences for individual alcoholism symptoms, and exploring these differences may lead to further insights into the nosology and etiology of alcohol-related problems.