Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus ( FOXP2 , lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 −9 ) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2 , lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 −9 ). Cannabis use disorder and cannabis use were genetically correlated ( r g 0·50, p=1·50 × 10 −21 ), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Serv...

In light of increasing cannabis use among pregnant women, the US Surgeon General recently issued an advisory against the use of marijuana during pregnancy.OBJECTIVE To evaluate whether cannabis use during pregnancy is associated with adverse outcomes among offspring. DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development Study, which recruited 11 875 children aged 9 to 11 years, as well as a parent or caregiver, from 22 sites across the United States between June 1, 2016, and October 15, 2018. EXPOSURE Prenatal cannabis exposure prior to and after maternal knowledge of pregnancy.MAIN OUTCOMES AND MEASURES Symptoms of psychopathology in children (ie, psychotic-like experiences [PLEs] and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index, and brain structure (ie, total intracranial volume, white matter volume, and gray matter volume). Covariates included familial (eg, income and familial psychopathology), pregnancy (eg, prenatal exposure to alcohol and tobacco), and child (eg, substance use) variables. RESULTS Among 11 489 children (5997 boys [52.2%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal cannabis exposure data, 655 (5.7%) were exposed to cannabis prenatally. Relative to no exposure, cannabis exposure only before (413 [3.6%]) and after (242 [2.1%]) maternal knowledge of pregnancy were associated with greater offspring psychopathology characteristics (ie, PLEs and internalizing, externalizing, attention, thought and, social problems), sleep problems, and body mass index, as well as lower cognition and gray matter volume (all |β| > 0.02; all false discovery rate [FDR]-corrected P < .03). Only exposure after knowledge of pregnancy was associated with lower birth weight as well as total intracranial volume and white matter volumes relative to no exposure and exposure only before knowledge (all |β| > 0.02; all FDR-corrected P < .04). When including potentially confounding covariates, exposure after maternal knowledge of pregnancy remained associated with greater PLEs and externalizing, attention, thought, and social problems (all β > 0.02; FDR-corrected P < .02). Exposure only prior to maternal knowledge of pregnancy did not differ from no exposure on any outcomes when considering potentially confounding variables (all |β| < 0.02; FDR-corrected P > .70). CONCLUSIONS AND RELEVANCEThis study suggests that prenatal cannabis exposure and its correlated factors are associated with greater risk for psychopathology during middle childhood. Cannabis use during pregnancy should be discouraged.

Genetic liability to substance use disorders can be parsed into loci conferring general and substance-specific addiction risk. We report a multivariate genome-wide association study that disaggregates general and substance-specific loci for problematic alcohol use, problematic tobacco use, and cannabis and opioid use disorders in a sample of 1,025,550 individuals of European and 92,630 individuals of African descent. Nineteen loci were genome-wide significant for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries PDE4B was significant (among others), suggesting dopamine regulation as a cross-trait vulnerability. The addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into the genetic architecture of general and substance-specific use disorder risk that may be leveraged as treatment targets.

Importance: In light of increasing cannabis use among pregnant women, the Surgeon General of the United States issued an advisory against the use of marijuana during pregnancy on August 29th, 2019. Objective: To determine whether cannabis use during pregnancy is associated with adverse outcomes among offspring. Design: Cross-sectional analysis of the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development (ABCD) study. Setting: Data were collected from 22 sites across the United States between 2016 and 2018. Participants: Children ages 9-11 (n=11,489) and their parent or caregiver. Exposure: Prenatal marijuana exposure prior to and following maternal knowledge of pregnancy. Main Outcomes and Measures: Child psychopathology symptomatology (i.e., psychotic-like experiences and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index (BMI), and brain structure (i.e., total intracranial volume, white matter volume, gray matter volume). Covariates included familial (e.g., income, familial psychopathology), pregnancy (e.g., prenatal vitamin use, whether the pregnancy was planned), and child (e.g., birth weight, substance use) variables. Results: Among 11,489 children (age 9.9±0.6 years; 47.78% female), 655 (5.70%) were prenatally exposed to cannabis in total. Marijuana use prior to (n=648; 5.64%) and following (n=242; 2.11%) maternal knowledge of pregnancy were associated with increased offspring psychopathology characteristics (i.e., psychotic-like experiences and internalizing, externalizing, attention, thought, social, and sleep problems) and BMI as well as reduced cognition, birth weight, and brain structure (i.e., total white and gray mater volumes; all psfdr<.007), but not gestational age at birth. Exposure following maternal knowledge of pregnancy remained significantly associated with psychopathology, cognition, and birth weight outcomes when including potentially confounding variables (all ps<0.046). All associations with exposure prior to maternal knowledge of pregnancy were nonsignificant when considering potentially confounding variables (all ps>0.06). Conclusions and Relevance: Prenatal cannabis exposure, and its correlated factors, may increase risk for psychopathology and reduced cognition during middle childhood as well as reduced birthweight. Consistent with recent recommendations by the Surgeon General, marijuana use during pregnancy should be discouraged.

Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci from published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent singlenucleotide polymorphisms were genome-wide significant (P < 5 × 10 -8 ) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis and 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.The lives lost, impacts on individuals and families, and socioeconomic costs attributable to substance use reflect a growing public health crisis 1 . For example, in the United States, 13.5% of deaths among young adults 2 are attributable to alcohol, smoking is the leading risk factor for mortality in males 3 , and the odds of dying by opioid overdose are greater than those of dying in a motor vehicle crash 4 . Despite the large impact of substance use and substance use disorders 5 , there is limited knowledge of the molecular genetic underpinnings of addiction broadly.