Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

ehaviors related to self-regulation, such as substance use disorders or antisocial behaviors, have far-reaching consequences for affected individuals, their families, communities and society at large 1,2 . Collectively, this group of correlated traits are classified as externalizing 3 . Twin studies have demonstrated that externalizing liability is highly heritable (~80%) 4,5 . To date, however, no large-scale molecular genetic studies have utilized the extensive degree of genetic overlap among externalizing traits to aid gene discovery, as most studies have focused on individual disorders 6 . For many high-cost, high-risk behaviors with an externalizing component-opioid use disorder and suicide attempts 7 being salient examples-there are limited genotyped cases available for gene discovery 8,9 .A complementary strategy to the single-disease approach is to study the shared genetic architecture across traits in multivariate analyses, which boosts statistical power by pooling data across

None.

No abstract

Studies testing the effect of single genetic variants on substance use have had modest success. This paper reviewed 39 studies using polygenic measures to test interaction with any type of environmental exposure (G×E) in alcohol, tobacco, and cannabis use. Studies using haplotype combinations, sum scores of candidate-gene risk alleles, and polygenic scores (PS) were included. Overall study quality was moderate, with lower ratings for the polygenic methods in the haplotype and candidate-gene score studies. Heterogeneity in investigated environmental exposures, genetic factors, and outcomes was substantial. Most studies ( N = 30) reported at least one significant G×E interaction, but overall evidence was weak. The majority ( N = 26) found results in line with differential susceptibility and diathesis-stress frameworks. Future studies should pay more attention to methodological and statistical rigor, and focus on replication efforts. Additional work is needed before firm conclusions can be drawn about the importance of G×E in the etiology of substance use. Electronic supplementary material The online version of this article (10.1007/s10519-019-09958-7) contains supplementary material, which is available to authorized users.