Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Cannabis and Depression: A Twin Model Approach to Co-morbidity.

Cannabis use disorder (CUD) co-occurs with major depressive disorder (MDD) more frequently than would be expected by chance. However, studies to date have not produced a clear understanding of the mechanisms underlying this co-morbidity. Genetically informative studies can add valuable insight to this problem, as they allow the evaluation of competing models of co-morbidity. This study uses data from the Australian Twin Registry to compare 13 co-morbidity twin models initially proposed by Neale and Kendler (Am J Hum Genet 57:935-953, 1995). The analysis sample comprised 2410 male and female monozygotic and dizygotic twins (average age 32) who were assessed on CUD and MDD using the SSAGA-OZ interview. Data were analyzed in OpenMx. Of the 13 different co-morbidity models, two fit equally well: CUD causes MDD and Random Multiformity of CUD. Both fit substantially better than the Correlated Liabilities model. Although the current study cannot differentiate between them statistically, these models, in combination, suggest that CUD risk factors may causally influence the risk to develop MDD, but only when risk for CUD is high.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

The association between childhood maltreatment, psychopathology, and adult sexual victimization in men and women: results from three independent samples.

BACKGROUND: Childhood maltreatment (CM) has consistently been linked with adverse outcomes including substance use disorders and adult sexual revictimization. Adult sexual victimization itself has been linked with psychopathology but has predominately been studied in women. The current investigation examines the impact of CM and co-occurring psychopathology on adult sexual victimization in men and women, replicating findings in three distinct samples. METHOD: We investigated the association between continuous CM factor scores and adult sexual victimization in the Childhood Trauma Study (CTS) sample (N = 2564). We also examined the unique relationship between childhood sexual abuse (CSA) and adult sexual victimization while adjusting for co-occurring substance dependence and psychopathology. We replicated these analyses in two additional samples: the Comorbidity and Trauma Study (CATS; N = 1981) and the Australian Twin-Family Study of Alcohol Use Disorders (OZ-ALC; N = 1537). RESULTS: Analyses revealed a significant association with CM factor scores and adult sexual victimization for both men and women across all three samples. The CSA factor score was strongly associated with adult sexual victimization after adjusting for substance dependence and psychopathology; higher odds ratios were observed in men (than women) consistently across the three samples. CONCLUSIONS: A continuous measure of CSA is independently associated with adult sexual trauma risk across samples in models that included commonly associated substance dependence and psychopathology as covariates. The strength of the association between this CSA measure and adult sexual victimization is higher in magnitude for men than women, pointing to the need for further investigation of sexual victimization in male community samples.

Natural course of cannabis use disorders.

BACKGROUND: Despite its importance as a public health concern, relatively little is known about the natural course of cannabis use disorders (CUDs). The primary objective of this research was to provide descriptive data on the onset, recovery and recurrence functions of CUDs during the high-risk periods of adolescence, emerging adulthood and young adulthood based on data from a large prospective community sample. METHOD: Probands (n = 816) from the Oregon Adolescent Depression Project (OADP) participated in four diagnostic assessments (T1-T4) between the ages of 16 and 30 years, during which current and past CUDs were assessed. RESULTS: The weighted lifetime prevalence of CUDs was 19.1% with an average onset age of 18.6 years. Although gender was not significantly related to the age of initial CUD onset, men were more likely to be diagnosed with a lifetime CUD. Of those diagnosed with a CUD episode, 81.8% eventually achieved recovery during the study period. Women achieved recovery significantly more quickly than men. The recurrence rate (27.7%) was relatively modest, and most likely to occur within the first 36 months following the offset of the first CUD episode. CUD recurrence was uncommon after 72 months of remission and recovery. CONCLUSIONS: CUDs are relatively common, affecting about one out of five persons in the OADP sample prior to the age of 30 years. Eventual recovery from index CUD episodes is the norm, although about 30% of those with a CUD exhibit a generally persistent pattern of problematic use extending 7 years or longer.

The role of conduct disorder in the relationship between alcohol, nicotine and cannabis use disorders.

BACKGROUND: Genetic influences contribute significantly to co-morbidity between conduct disorder and substance use disorders. Estimating the extent of overlap can assist in the development of phenotypes for genomic analyses. METHOD: Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose co-twin was not interviewed (aged 24-37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic influences shared with conduct disorder. RESULTS: Additive genetic (a(2) = 0.48-0.65) and non-shared environmental factors explained variance in substance use disorders. Familial effects on conduct disorder were due to additive genetic (a(2) = 0.39) and shared environmental (c(2) = 0.15) factors. All substance use disorders were influenced by shared genetic factors (rg = 0.38-0.56), with all genetic overlap between substances attributable to genetic influences shared with conduct disorder. Genes influencing individual substance use disorders were also significant, explaining 40-73% of the genetic variance per substance. CONCLUSIONS: Among substance users in this sample, the well-documented clinical co-morbidity between conduct disorder and substance use disorders is primarily attributable to shared genetic liability. Interventions targeted at generally reducing deviant behaviors may address the risk posed by this shared genetic liability. However, there is also evidence for genetic and environmental influences specific to each substance. The identification of these substance-specific risk factors (as well as potential protective factors) is critical to the future development of targeted treatment protocols.

A genetic perspective on the proposed inclusion of cannabis withdrawal in DSM-5.

BACKGROUND: Various studies support the inclusion of cannabis withdrawal in the diagnosis of cannabis use disorder (CUD) in the upcoming DSM-5. The aims of the current study were to (1) estimate the prevalence of DSM-5 cannabis withdrawal (criterion B), (2) estimate the role of genetic and environmental influences on individual differences in cannabis withdrawal and (3) determine the extent to which genetic and environmental influences on cannabis withdrawal overlap with those on DSM-IV-defined abuse/dependence. METHOD: The sample included 2276 lifetime cannabis-using adult Australian twins. Cannabis withdrawal was defined in accordance with criterion B of the proposed DSM-5 revisions. Cannabis abuse/dependence was defined as endorsing one or more DSM-IV criteria of abuse or three or more dependence criteria. The classical twin model was used to estimate the genetic and environmental influences on variation in cannabis withdrawal, along with its covariation with abuse/dependence. RESULTS: Of all the cannabis users, 11.9% met criteria for cannabis withdrawal. Around 50% of between-individual variation in withdrawal could be attributed to additive genetic variation, and the rest of the variation was mostly due to non-shared environmental influences. Importantly, the genetic influences on cannabis withdrawal almost completely (99%) overlapped with those on abuse/dependence. CONCLUSIONS: We have shown that cannabis withdrawal symptoms exist among cannabis users, and that cannabis withdrawal is moderately heritable. Genetic influences on cannabis withdrawal are the same as those affecting abuse/dependence. These results add to the wealth of literature that recommends the addition of cannabis withdrawal to the diagnosis of DSM-5 CUD.

Cannabis or alcohol first? Differences by ethnicity and in risk for rapid progression to cannabis-related problems in women.

BACKGROUND: Initiation of cannabis use typically follows alcohol use, but the reverse order does occur and is more common for African-Americans (AAs) than European-Americans (EAs). The aim of this study was to test for differences in the order of initiation of cannabis and alcohol use between AA and EA women and to determine whether order and ethnicity contribute independently to risk for rapid progression to cannabis-related problems. Method Data were drawn from structured psychiatric interviews of 4102 women (mean age = 21.6 years), 3787 from an all-female twin study and 315 from a high-risk family study; 18.1% self-identified as AA, 81.9% as EA. Ethnicity and order of initiation of cannabis and alcohol use were modeled as predictors of transition time from first use to onset of cannabis use disorder symptom(s) using Cox proportional hazards regression analyses. RESULTS: AA women were nearly three times as likely as EA women to initiate cannabis use before alcohol use. Using cannabis before alcohol [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.08-1.93] and AA ethnicity (HR 1.59, 95% CI 1.13-2.24) were both associated with rapid progression from first use to cannabis symptom onset even after accounting for age at initiation and psychiatric risk factors. CONCLUSIONS: The findings indicate that AA women are at greater risk for rapid development of cannabis-related problems than EA women and that this risk is even higher when cannabis use is initiated before alcohol use. Prevention programs should be tailored to the various patterns of cannabis use and relative contributions of risk factors to the development of cannabis-related problems in different ethnic groups.

Do shared etiological factors contribute to the relationship between sexual orientation and depression?

BACKGROUND: Gays, lesbians and bisexuals (i.e. non-heterosexuals) have been found to be at much greater risk for many psychiatric symptoms and disorders, including depression. This may be due in part to prejudice and discrimination experienced by non-heterosexuals, but studies controlling for minority stress, or performed in very socially liberal countries, suggest that other mechanisms must also play a role. Here we test the viability of common cause (shared genetic or environmental etiology) explanations of elevated depression rates in non-heterosexuals. METHOD: A community-based sample of adult twins (n=9884 individuals) completed surveys investigating the genetics of psychiatric disorder, and were also asked about their sexual orientation. Large subsets of the sample were asked about adverse childhood experiences such as sexual abuse, physical abuse and risky family environment, and also about number of older brothers, paternal and maternal age, and number of close friends. Data were analyzed using the classical twin design. RESULTS: Non-heterosexual males and females had higher rates of lifetime depression than their heterosexual counterparts. Genetic factors accounted for 31% and 44% of variation in sexual orientation and depression respectively. Bivariate analysis revealed that genetic factors accounted for a majority (60%) of the correlation between sexual orientation and depression. In addition, childhood sexual abuse and risky family environment were significant predictors of both sexual orientation and depression, further contributing to their correlation. CONCLUSIONS: Non-heterosexual men and women had elevated rates of lifetime depression, partly due to shared etiological factors, although causality cannot be definitively resolved.

Item response modeling of DSM-IV mania symptoms in two representative US epidemiological samples.

BACKGROUND: There is considerable debate surrounding the effective measurement of DSM-IV symptoms used to assess manic disorders in epidemiological samples. METHOD: Using two nationally representative datasets, the National Epidemiological Survey of Alcohol and Related Conditions (NESARC, n=43,093 at wave 1, n=34,653 at 3-year follow-up) and the National Comorbidity Survey - Replication (NCS-R, n=9282), we examined the psychometric properties of symptoms used to assess DSM-IV mania. The predictive utility of the mania factor score was tested using the 3-year follow-up data in NESARC. RESULTS: Criterion B symptoms were unidimensional (single factor) in both samples. The symptoms assessing flight of ideas, distractibility and increased goal-directed activities had high factor loadings (0.70-0.93) with moderate rates of endorsement, thus providing good discrimination between individuals with and without mania. The symptom assessing grandiosity performed less well in both samples. The quantitative mania factor score was a good predictor of more severe disorders at the 3-year follow-up in the NESARC sample, even after controlling for a past history of DSM-IV diagnosis of manic disorder. CONCLUSIONS: These analyses suggest that questions based on some DSM symptoms effectively discriminate between individuals at high and low liability to mania, but others do not. A quantitative mania factor score may aid in predicting recurrence for patients with a history of mania. Methods for assessing mania using structured interviews in the absence of clinical assessment require further refinement.

Comorbidity between depressive disorders and nicotine dependence in a cohort of 16-year-olds.

BACKGROUND: There has been growing interest in the associations between cigarette smoking and symptoms of depression. This study documents the comorbidity between depression and nicotine dependence in a birth cohort of 16-year-olds and examines the extent to which comorbidity between depression and nicotine dependence could be explained by risk factors associated with both outcomes. METHODS: Data were gathered during the course of a 16-year longitudinal study of a birth cohort of 947 New Zealand children for (1) depressive disorders and nicotine dependence at age 16 years; and (2) prospectively measured risk factors including family social position, family history of criminality, parental smoking, life events, parental attachment, conduct problems, self-esteem, and affiliations with delinquent peers. RESULTS: There was evidence of moderate to strong comorbidity between depression and nicotine dependence at age 16 years; teenagers with a depressive disorder had odds of nicotine dependence that were 4.6 times those of teenagers without depressive disorder. Analyses using logistic regression and log-linear modeling methods revealed that a substantial component of the comorbidity between depression and nicotine dependence was explained by common or correlated risk factors associated with both outcomes. After adjustment for common or correlated risk factors, the adjusted odds ratio between depression and nicotine dependence was 2.3. CONCLUSIONS: Comorbidities between depression and nicotine dependence seem to be well established by the age of 16 years. Much of this comorbidity can be explained by common or correlated risk factors associated with depression or nicotine dependence.

The relationship between cannabis involvement and suicidal thoughts and behaviors.

BACKGROUND: In the present study, we examined the relationship between cannabis involvement and suicidal ideation (SI), plan and attempt, differentiating the latter into planned and unplanned attempt, taking into account other substance involvement and psychopathology. METHODS: We used two community-based twin samples from the Australian Twin Registry, including 9583 individuals (58.5% female, aged between 27 and 40). The Semi-Structured Assessment of the Genetics of Alcoholism (SSAGA) was used to assess cannabis involvement which was categorized into: (0) no cannabis use (reference category); (1) cannabis use only; (2) 1-2 cannabis use disorder symptoms; (3) 3 or more symptoms. Separate multinomial logistic regression analyses were conducted for SI and suicide attempt with or without a plan. Twin analyses examined the genetic overlap between cannabis involvement and SI. RESULTS: All levels of cannabis involvement were related to SI, regardless of duration (odds ratios [ORs]=1.28-2.00, p<0.01). Cannabis use and endorsing ≥3 symptoms were associated with unplanned (SANP; ORs=1.95 and 2.51 respectively, p<0.05), but not planned suicide attempts (p>0.10). Associations persisted even after controlling for other psychiatric disorders and substance involvement. Overlapping genetic (rG=0.45) and environmental (rE=0.21) factors were responsible for the covariance between cannabis involvement and SI. CONCLUSIONS: Cannabis involvement is associated, albeit modestly, with SI and unplanned suicide attempts. Such attempts are difficult to prevent and their association with cannabis use and cannabis use disorder symptoms requires further study, including in different samples and with additional attention to confounders.

Alcohol misuse and adolescent sexual behaviors and risk taking.

OBJECTIVE: The aims of this study were to examine the associations between alcohol misuse and measures of early onset sexual activity and sexual risk-taking behaviors during adolescence and the extent to which any association between these two sets of behaviors could be explained by common risk factors that predisposed individuals to both outcomes. METHODS: Data were gathered during the course of a 16-year longitudinal study of a birth cohort of 953 New Zealand children and included: (1) self-report measures of early onset sexual activity (before the age of 16 years), multiple partners (three or more), and unprotected intercourse during the interval from 15 to 16 years; and (2) prospectively measured risk factors, including social background, childhood adversity, novelty seeking, and affiliations with delinquent peers. RESULTS: Adolescents who reported misusing alcohol had odds of early onset sexual activity, multiple partners, and unprotected intercourse that were 6.1 to 23.0 times those of young people who did not misuse alcohol. After adjustment for common or correlated risk factors, the adjusted odds ratios between alcohol misuse and early onset sexual activity and unprotected intercourse were reduced but remained statistically significant. However, no significant association between alcohol misuse and multiple partners was found after adjustment for common or correlated risk factors. CONCLUSIONS: Much of the apparent association between alcohol misuse and teenage sexual activity and risk taking seems to arise through the influence of common family, individual, and peer factors. However, alcohol misuse may also place teenagers at greater risk of initiating early onset sexual intercourse and engaging in unprotected intercourse.

Maternal smoking before and after pregnancy: effects on behavioral outcomes in middle childhood.

OBJECTIVE: The aim of this research was to examine the extent to which maternal smoking before and after pregnancy was associated with childhood disruptive behaviors when due allowance was made for potentially confounding factors which may have been associated with both maternal smoking habits and childhood problem behaviors. METHODS: During the course of a 15-year longitudinal study of a birth cohort of 1265 New Zealand children, the following measures were obtained: (1) measures of daily cigarette intake during pregnancy and after pregnancy; (2) measures of childhood disruptive behaviors including conduct problems and attention deficit behaviors based on both maternal and teacher report data; and (3) measures of a series of potentially confounding family, social, parental, and related factors. RESULTS: Before adjustments for confounding, maternal smoking both before and after pregnancy was found to be associated with significant increases in rates of childhood problem behaviors: children whose mothers smoked in excess of 20 cigarettes per day had mean problem behavior scores that were between 0.16 and 0.56 standard deviations higher than those of children whose mothers were nonsmokers. The results were then adjusted using regression methods to take account of (1) correlations between pregnancy and postpregnancy smoking and (2) potentially confounding factors. The results of regression adjustment suggested that maternal smoking during pregnancy was associated with small but statistically detectable increases in rates of childhood problem behaviors, with children whose mothers smoked in excess of 20 cigarettes per day having mean scores that were 0.10 to 0.36 standard deviations higher than those of the offspring of nonsmokers, even after adjustment for a series of confounding factors. However, smoking after pregnancy was not significantly associated with increased rates of childhood problem behavior after adjustment for sources of confounding. CONCLUSION: The results are generally consistent with the hypothesis that smoking during pregnancy may be associated with small but detectable increases in the risks of problem behaviors in childhood. This suggests that possible adverse effects on childhood behavioral adjustment should be added to the growing list of adverse consequences of parental smoking for childhood health and well-being.

Childhood circumstances, adolescent adjustment, and suicide attempts in a New Zealand birth cohort.

OBJECTIVE: To estimate the prevalence of attempted suicide during adolescence in a birth cohort of New Zealand children studied to the age of 16 years and to examine the relationships among adolescent problems of adjustment, psychopathology, childhood circumstances, and risks of adolescent suicide attempts. METHOD: Attempted suicide, adolescent problems of adjustment, psychopathology, and childhood circumstances were assessed as part of a longitudinal study of a birth cohort of 954 New Zealand children studied at annual intervals to the age of 16 years. RESULTS: By 16 years, 3.0% of the sample (4.2% of girls and 1.9% of boys) reported having made a suicide attempt. There were strong associations between attempted suicide and rates of adolescent problem behaviors or psychopathology; teenagers having problems of adjustment or psychiatric disorders were up to 22 times more likely to attempt suicide. Risks of attempted suicide were also higher among children from disadvantaged or dysfunctional family backgrounds. A loglinear model fitted to the measures of attempted suicide, adolescent psychopathology, problems of adjustment, and childhood circumstances suggested the presence of a causal chain process in which childhood problems were significantly (p < .005) related to increased risks of later psychopathology and problems of personal adjustment which were, in turn, related to significantly (p < .05) increased rates of attempted suicide. CONCLUSIONS: A common pathway that leads to increased vulnerability to suicidal behavior involves early disadvantageous childhood and family circumstances, which lead to increased risks of adolescent psychopathology and problems of adjustment, which lead to increased risks and vulnerability to adolescent suicidal behaviors.

Suicide attempts and suicidal ideation in a birth cohort of 16-year-old New Zealanders.

OBJECTIVE: To describe the prevalence of suicide attempts and suicidal ideation in a birth cohort of New Zealand children studied to the age of 16 years; to examine the extent to which risks of suicide attempts and suicidal ideation varied with levels of adolescent psychopathology, problems of adjustment, and exposure to adverse conditions during childhood; and to examine the extent to which those attempting suicide could be distinguished from those reporting suicidal ideation alone. METHOD: Data were gathered on suicide attempts, suicidal ideation, psychiatric diagnoses, adjustment problems, and childhood factors during the course of a 16-year longitudinal study of a birth cohort of New Zealand children. RESULTS: Twelve percent of this cohort reported suicidal ideation before the age of 16 years and 3% attempted suicide. The extent to which young people expressed suicidal tendencies varied with the extent to which the young person met criteria for psychiatric disorder, the extent of adjustment problems, and the extent to which the young person had been exposed to adverse family circumstances. Those attempting suicide were distinguished from those reporting suicidal ideation by having significantly higher rates of psychopathology (p < .05), higher rates of adjustment problems (p < .005), and greater exposure to childhood and family adversity (p < .05). CONCLUSION: The results of this analysis were consistent with a dimensional model of suicidal behaviors in which those attempting suicide are distinguished from those reporting suicidal ideation alone by having a greater burden of psychosocial risk factors including psychiatric disorder, adjustment problems, and adverse childhood circumstances.

Parental separation, adolescent psychopathology, and problem behaviors.

OBJECTIVE: This paper examines the effects of parental separation on the occurrence of adolescent psychopathology and problem behaviors at age 15 years. METHODS: Data collected during the course of a 15-year longitudinal study were used to examine a sample of 935 children with respect to exposure to parental separation during childhood, measures of adolescent psychopathology and problem behaviors at age 15 years, and prospectively collected confounding factors. RESULTS: Children exposed to parental separation during childhood had elevated risks of a range of adolescent problems, including substance abuse or dependence, conduct or oppositional disorders, mood and anxiety disorders, and early-onset sexual activity. However, adjustment for confounding factors explained a large amount of the increased risks of adolescent disorder, and after adjustment for confounders the odds ratios between exposure to parental separation and adolescent outcomes ranged from 1.07 to 3.32 with a median value of 1.46. The ways in which boys and girls responded to parental separation were similar. CONCLUSIONS: While the results suggested that children exposed to parental separation had increased risks of adolescent problems, much of this association appeared to be spurious and arose from confounding social and contextual factors that were present in the child's family before parental separation. However, even after such control, the results suggested that exposure to parental separation during childhood was associated with small but detectable increases in risks of adolescent conduct disorder, mood disorder, and substance abuse disorders.

Structure of DSM-III-R criteria for disruptive childhood behaviors: confirmatory factor models.

OBJECTIVE: The aims of this analysis were to examine the extent to which DSM-III-R criteria for disruptive behavior patterns were consistent with the system of diagnoses proposed. Particular attention was paid to (1) whether oppositional defiant disorder is factorially distinct from conduct disorder (CD) and (2) the extent to which CD can be further classified into overt and covert CD behaviors. METHOD: Data were gathered on DSM-III-R criteria for disruptive behavior patterns for a sample of 739 New Zealand 15-year-olds using data provided by parental and self-report. These data were supplemented by officially recorded police contact data. RESULTS: Application of methods of confirmatory factor analysis suggested that the diagnostic criteria in DSM-III-R reflected a constellation of distinct but highly correlated behavioral domains, with these domains corresponding to oppositional defiant disorder, overt CD (aggression, violence), covert CD (theft, dishonesty), and attention-deficit hyperactivity disorder behavior. Results of second-order factor analysis methods suggested that these dimensions reflected two general higher-order factors, with the first factor reflecting the extent to which the individual displayed behavioral symptoms of oppositional defiant disorder and attention-deficit hyperactivity disorder and the second reflecting the extent to which the individual expressed antisocial, conduct-disordered behaviors. CONCLUSIONS: The results of confirmatory factor analysis generally support and validate the diagnostic classifications proposed in DSM-III-R but suggest possible refinements that draw distinctions between overt and covert expressions of CD.