Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Marijuana is one of the most commonly used drugs in the United States, and use during adolescence-when the brain is still developing-has been proposed as a cause of poorer neurocognitive outcome. Nonetheless, research on this topic is scarce and often shows conflicting results, with some studies showing detrimental effects of marijuana use on cognitive functioning and others showing no significant long-term effects. The purpose of the present study was to examine the associations of marijuana use with changes in intellectual performance in two longitudinal studies of adolescent twins (n = 789 and n = 2,277). We used a quasiexperimental approach to adjust for participants' family background characteristics and genetic propensities, helping us to assess the causal nature of any potential associations. Standardized measures of intelligence were administered at ages 9-12 y, before marijuana involvement, and again at ages 17-20 y. Marijuana use was self-reported at the time of each cognitive assessment as well as during the intervening period. Marijuana users had lower test scores relative to nonusers and showed a significant decline in crystallized intelligence between preadolescence and late adolescence. However, there was no evidence of a dose-response relationship between frequency of use and intelligence quotient (IQ) change. Furthermore, marijuana-using twins failed to show significantly greater IQ decline relative to their abstinent siblings. Evidence from these two samples suggests that observed declines in measured IQ may not be a direct result of marijuana exposure but rather attributable to familial factors that underlie both marijuana initiation and low intellectual attainment.M arijuana is one of the most commonly used drugs in the United States, with a lifetime use prevalence of 50% (1, 2). Despite this, research on the long-term effects of marijuana use is scarce compared with that of other illicit substances. Changing cultural attitudes toward marijuana have recently led to social and legal acceptance of recreational use (3, 4), making research on the potential consequences particularly salient.Previous research has shown that marijuana use can have a high societal cost through increased unemployment, absenteeism, decreased productivity, and increased rates of crime and incarceration (5-8). Given that about 19% of youth and young adults (ages 18-25 y) in the United States have used marijuana in the past month (9), the potential impact is nontrivial. There is evidence to suggest that the adolescent brain may be particularly vulnerable, especially with regard to neurocognitive functioning (10, 11). Marijuana use in adolescence, when the brain is still undergoing major developmental changes, has been associated with decreased intelligence (12, 13), reduced memory (13-15), poorer attention (16-18), and lower verbal ability (19-21). However, these findings come from cross-sectional studies, where the temporal ordering of cause and effect is uncertain. For longitudinal studies examining marijuana use and ch...

To determine if drinking behavior in adolescence provides a "gateway" leading to the misuse of other psychoactive substances and antisocial behavior, we genotyped 180 Asian adolescent adoptees to determine if they inherited the deficient from of the aldehyde dehydrogenase 2 (ALDH2) enzyme that is important in the metabolism of alcohol. Based on the gateway model, we hypothesized that those with normal enzyme activity (70% of the sample) who began to misuse alcohol would also misuse other drugs and display antisocial tendencies. Those with the enzyme deficiency (30%), because they experience unpleasant side effects associated with drinking, were expected to show less evidence of alcohol misuse and thus be less likely to progress to the misuse of other substances or engage in antisocial acts. Consistent with previous research, we found that ALDH2 deficiency was significantly associated with lower rates of drinking and getting drunk but not with ever having tried alcohol. Contrary to the gateway model, we found no evidence that ALDH2 deficiency was associated with lower rates of nonalcohol substance use or antisociality. Finally, in an examination of factors that may moderate the impact of the metabolic protection because of ALDH2 deficiency, we identified siblings rather than parents as the major source of familial environmental effect on adolescent drinking.

Background In the aldehyde dehydrogenase 2 (ALDH2) gene, the ALDH2*2 allele, prevalent in East Asian populations, encodes an enzyme with severely reduced activity, thereby disrupting the normal metabolism of alcohol. Possession of the ALDH2*2 allele has been repeatedly shown to be associated with lower risk for alcohol dependence, and reduced alcohol use. However, relatively few studies have considered whether the magnitude of the effect of ALDH2 polymorphism upon drinking is related to developmental stage, or varies by environmental context. Methods In a longitudinally assessed sample of 356 adopted adolescents and young adults of East Asian descent, we examined the progression over time of the relationship between ALDH2 genotype and multiple measures of drinking behavior. We also sought to determine whether the environmental influences of non-biological parent and elder sibling alcohol use and misuse, as well as deviant peer behavior, moderated the effect of ALDH2 genotype upon alcohol use. Results Across all measures of alcohol use, the association between ALDH2*2 allele possession and reduced drinking went from negligible to moderate between mid-adolescence and early adulthood. A combined index of adoptive parent alcohol use and misuse consistently moderated the protective effect of the ALDH2*2 allele across measures of quantity and frequency of alcohol use, and symptomology, such that high parental alcohol use and misuse reduced the protective effect of the ALDH2*2 allele, while low parental alcohol use and misuse enhanced the effect of the allele. Neither a combined index of elder sibling alcohol use and misuse, nor deviant peer behavior were consistently related to the effect of ALDH2 genotype. Conclusions The protective effect of the ALDH2*2 allele increases over the course of adolescence and young adulthood and is modified by the environmental influence of parental alcohol use and misuse. As such, ALDH2 provides a model system for exploring the nature of gene-environment interplay across development.

Aims To determine whether early adolescent alcohol use contributes to adult alcohol use, misuse, and other adult substance-related and social outcomes. Design In a longitudinal study of twins assessed at target ages 11, 14, and 24, two techniques adjusted for confounding factors: a propensity score (PS) adjusting for the effects of measured background covariates, and cotwin control (CTC) adjusting for confounding by unmeasured (including genetic) factors shared within early alcohol exposure-discordant pairs. Setting The community-based Minnesota Twin Family Study. Participants 1512 (760 female, 752 male) twins. Measurements Early adolescent alcohol exposures, adult substance-related and social outcomes, and background variables reflecting behavioral, familial, and environmental characteristics. Findings Background covariates unbalanced between those with and without early alcohol exposure were balanced through PS-based weighting, leaving several adult outcomes related to substance use or social functioning remaining significantly associated with early alcohol exposure.Likewise, the within-pair individual-level component of a CTC indicated that early alcohol-exposed twins had higher risk than their non-exposed cotwins for several, but not all, of the same adult outcomes. For example, early alcohol use was associated with an adult index of alcohol use in both PS-weighted (β = 0.57, p < 0.001) and CTC (β = 0.21, p = 0.031 ) analyses. Conclusions Early alcohol exposures predict adult alcohol problems and related outcomes, despite stringent adjustment for measured and non-measured sources of potential confounding using PS and CTC. Contrasting the methods indicated that exposure effect estimates from PS application were likely biased by unmeasured confounding factors.