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.

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.

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 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.

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.

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.

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.

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.

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.

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.

Differential criterion functioning of alcohol use symptomatology in major depressive disorder?

BACKGROUND: Major depressive disorder (MDD) and alcohol use disorders (AUDs) are among the most prevalent psychiatric disorders and are frequently co-morbid. However, some component of this co-morbidity may be artifactual and arise from the influence of current mental state on self-reports of AUD. METHOD: This study examined whether past-year MDD is associated with differential criterion functioning (DCF) in reports of AUD symptomatology in male and female participants in the National Epidemiological Survey on Alcohol and Related Conditions (NEASRC). RESULTS: Reports of past-year AUD symptomatology were adequately summarized by a single-factor model in which each of the 11 abuse and dependence criteria had high factor loadings (0.71-0.93) and did not vary between men and women after allowing for threshold differences. Co-morbid MDD was associated with higher AUD mean scores. There was some evidence for DCF with past-year MDD being associated with a lower endorsement of use in hazardous situations among men whereas women with MDD were more likely to endorse both social/interpersonal problems and emotional/physical problems. CONCLUSIONS: Several items assessing AUD display DCF in the presence of MDD. While these findings highlight the need to consider the possibility that mental state can influence reporting of psychiatric symptoms and potentially inflate estimates of co-morbidity, they suggest that only a negligible component of the co-morbidity between MDD and AUDs can be attributed to over-reporting of alcohol symptomatology conditional on current MDD.

Psychometric properties of DSM assessments of illicit drug abuse and dependence: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

BACKGROUND: DSM-IV criteria for illicit drug abuse and dependence are largely based on criteria developed for alcohol use disorders and there is a lack of research evidence on the psychometric properties of these symptoms when applied to illicit drugs. METHOD: This study utilizes data on abuse/dependence criteria for cannabis, cocaine, stimulants, sedatives, tranquilizers, opiates, hallucinogens and inhalants from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC, n=43 093). Analyses included factor analysis to explore the dimensionality of illicit drug abuse and dependence criteria, calculation of item difficulty and discrimination within an item response framework and a descriptive analysis of 'diagnostic orphans': individuals meeting criteria for 1-2 dependence symptoms but not abuse. Rates of psychiatric disorders were compared across groups. RESULTS: Results favor a uni-dimensional construct for abuse/dependence on each of the eight drug classes. Factor loadings, item difficulty and discrimination were remarkably consistent across drug categories. For each drug category, between 29% and 51% of all individuals meeting criteria for at least one symptom did not receive a formal diagnosis of either abuse or dependence and were therefore classified as 'orphans'. Mean rates of disorder in these individuals suggested that illicit drug use disorders may be more adequately described along a spectrum of severity. CONCLUSIONS: While there were remarkable similarities across categories of illicit drugs, consideration of item difficulty suggested that some alterations to DSM regarding the relevant severity of specific abuse and dependence criteria may be warranted.

Contrasting models of genetic co-morbidity for cannabis and other illicit drugs in adult Australian twins.

BACKGROUND: The use of cannabis and other illicit drugs (OIDs) and their co-morbid misuse are frequently reported in the literature. Correlated vulnerabilities and causal or gateway influences have been implicated in this association. We investigated the source of this co-morbidity between cannabis use (experimentation, early and repeated use, and problems) and OID experimentation and problems using genetic models proposed by Neale and Kendler (American Journal of Human Genetics 1995, 57, 935-953). METHOD: In a sample of 4152 same-sex male and female adult Australian twin individuals, we fit 13 genetically informative models of co-morbidity to data on experimentation, early use, repeated use of cannabis and co-morbid OID experimentation, and to abuse/dependence (A/D) problems with cannabis and OIDs. RESULTS: Model-fitting results suggest that common genetic, shared and unique environmental factors are responsible for the association between cannabis experimentation, early use, repeated use and A/D problems and OID experimentation or problems. The liability causation model, which is a reduced form of the correlated vulnerabilities model, also fit very well. In women, we found evidence for high-risk cannabis experimenters and repeated users to be at increased risk for OID experimentation, despite being below the risk threshold on the liability distribution for OID experimentation (extreme multiformity). CONCLUSIONS: Co-morbid cannabis and OID use and misuse are due partly to a common predisposition to substance use disorders. Putative causal effects could not be ruled out. These models warrant further research, so that features of the correlated vulnerabilities model and the gateway models can be studied jointly in a single series of adaptive nested models.

Patterns of association between alcohol consumption and symptoms of depression and anxiety in young adults.

AIMS: Recent epidemiological findings indicate that non-drinkers as well as hazardous/harmful drinkers experience higher levels of distress than moderate drinkers. Little is known about the age at which this develops. This paper examines levels of affect, depression and anxiety over the full range of alcohol consumption in young adults. DESIGN: Cross-sectional findings from the first wave of a prospective, longitudinal study are presented. PARTICIPANTS: The general population sample comprised of 2404 young adults (aged 20-24 years). living in the Canberra region. Measures included: the Goldberg Depression and Anxiety scales, the Positive and Negative Affect Schedule, and the Alcohol Use Disorders Identification Test. FINDINGS: For men, both non/occasional and hazardous/harmful consumption were associated with lower levels of positive affect and higher levels of anxiety and depression. The higher levels of distress evident for male abstainers were related to being less extroverted and less healthy and not to past hazardous/harmful alcohol consumption, current tobacco or marijuana use. For women, only hazardous/harmful drinkers were found to have higher levels of depression and negative affect. Hazardous/harmful consumption was related to using marijuana, tobacco and recent stressful events in both men and women. CONCLUSIONS: Higher levels of distress are already evident in male non-drinkers in early adulthood. The findings counter theories that distress in non-drinkers is due to past hazardous/harmful alcohol consumption, marijuana or tobacco use, or characteristics in common with hazardous/harmful drinkers. Alcohol use disorders and mental health problems are pertinent issues for young adults. However, more understanding is needed of the experiences of non-drinkers in an alcohol consuming culture.

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.

Attention deficit hyperactivity disorder and substance use disorders: Is there a causal link?

Attention-deficit hyperactivity disorder (ADHD), characterized by restless, inattentive and hyperactive behaviours, is a relatively common childhood disorder that affects approximately 5% of the general population. There has been controversy about whether ADHD increases risks of developing substance use disorders. The available evidence suggests that, in the absence of conduct disorder, ADHD is not associated with an increased risk of substance use problems in males. There is only limited evidence on the role of ADHD in the aetiology of substance use disorders among females. While ADHD has traditionally been considered as a childhood disorder, it may also occur in adults; research needs to examine the extent to which ADHD in adulthood increases the risk of substance use disorders.