Daniel E. Irons

Impact of adolescent marijuana use on intelligence : Results from two longitudinal twin studies

Significance Marijuana is the most commonly used recreational drug in the United States. Some studies suggest that marijuana use in adolescence is linked to declines in intellectual functioning. Because of the infeasibility of studying this phenomenon experimentally, it is unclear whether the association can be causally attributed to marijuana use itself or is instead the result of confounding factors. We approach this issue quasiexperimentally using longitudinal samples of adolescent twins. Among twin pairs discordant for marijuana use, we assessed intelligence quotient (IQ) score changes while adjusting for the effects of genetic influences and other factors shared by members of the same twin pair. Results suggest that familial confounds underlie the association between adolescent marijuana use and declining IQ scores. 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.

Harsh Discipline, Childhood Sexual Assault, and MAOA Genotype: An Investigation of Main and Interactive Effects on Diverse Clinical Externalizing Outcomes

We studied the impact of MAOA genotype, childhood sexual assault, and harsh discipline on clinical externalizing symptoms (substance problems, adult antisocial behavior, and conduct disorder). Participants were 841 individual twins from the Minnesota Twin Family Study assessed through age 25. MAOA genotype was not associated with differences in any phenotype, nor was there a significant interaction between MAOA and harsh discipline for any phenotype or a significant interaction between MAOA and childhood sexual assault for substance problems. We found evidence that childhood sexual assault interacted with MAOA genotype to predict antisocial behavior and conduct disorder symptoms. Individuals with the low MAOA activity genotype who reported childhood sexual assault had more symptoms than individuals with either the high MAOA activity genotype and/or no history of childhood sexual assault. These findings suggest that the previously reported interaction between MAOA and childhood maltreatment may be specific to the antisocial subset of externalizing disorders.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium

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.

In search of rare variants: Preliminary results from whole genome sequencing of 1,325 individuals with psychophysiological endophenotypes

Whole genome sequencing was completed on 1,325 individuals from 602 families, identifying 27 million autosomal variants. Genetic association tests were conducted for those individuals who had been assessed for one or more of 17 endophenotypes (N range = 802-1,185). No significant associations were found. These 27 million variants were then imputed into the full sample of individuals with psychophysiological data (N range = 3,088-4,469) and again tested for associations with the 17 endophenotypes. No association was significant. Using a gene-based variable threshold burden test of nonsynonymous variants, we obtained five significant associations. These findings are preliminary and call for additional analysis of this rich sample. We argue that larger samples, alternative study designs, and additional bioinformatics approaches will be necessary to discover associations between these endophenotypes and genomic variation.

Developmental Trajectory and Environmental Moderation of the Effect of ALDH2 Polymorphism on Alcohol Use

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 nonbiological 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 the 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 was 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.

Tests of the effects of adolescent early alcohol exposures on adult outcomes

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 years, two techniques adjusted for confounding factors: a propensity score (PS) adjusting for the effects of measured background covariates and co-twin 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 A total of 1512 (50.3% female) 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. Similarly, the within-pair individual-level component of a CTC indicated that early alcohol-exposed twins had higher risk than their non-exposed co-twins 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 propensity score and co-twin control. Contrasting the methods indicated that exposure effect estimates from PS application were likely biased by unmeasured confounding factors.

In search of rare variants

Whole genome sequencing was completed on 1,325 individuals from 602 families, identifying 27 million autosomal variants. Genetic association tests were conducted for those individuals who had been assessed for one or more of 17 endophenotypes (N range = 802-1,185). No significant associations were found. These 27 million variants were then imputed into the full sample of individuals with psychophysiological data (N range = 3,088-4,469) and again tested for associations with the 17 endophenotypes. No association was significant. Using a gene-based variable threshold burden test of nonsynonymous variants, we obtained five significant associations. These findings are preliminary and call for additional analysis of this rich sample. We argue that larger samples, alternative study designs, and additional bioinformatics approaches will be necessary to discover associations between these endophenotypes and genomic variation.

Gamma-aminobutyric acid system genes--no evidence for a role in alcohol use and abuse in a community-based sample.

BACKGROUND While twin and adoption studies point to substantial genetic influence upon alcohol use, dependence, and other alcohol-related phenotypes, few of the genes underlying variation in these phenotypes have been identified. Markers in genes related to GABAergic activity-a system integral to many of alcohols biological effects-have been implicated in alcohol use and alcohol-related psychopathology in linkage and association studies. METHODS Using multiple methods, we conducted a comprehensive examination of the effects of markers in γ-aminobutyric acid (GABA) system genes in a community-based sample of 7,224 individuals assessed in early and middle adulthood. In addition to testing the effect of individual single nucleotide polymorphism (SNP) markers on alcohol-related phenotypes, we computed a polygenic score reflecting the aggregated effects of multiple GABA system SNPs. We also estimated the variance in alcohol-related phenotypes attributable to all GABA system markers considered simultaneously and conducted gene-based association tests. RESULTS No method produced results indicative of an effect of GABA system variants on measures of alcohol use or misuse. CONCLUSIONS These results reflect alcohol-related behaviors in a population-representative sample, many of whom are still in adolescence, and in which the incidence of heavy drinking and alcohol-related symptomatology are relatively low. Contrasted with existing studies of the association between alcohol use and GABA system genes, our results suggest that the relationship may be limited to particular contexts, such as when accompanied by polysubstance abuse or a familial history of alcoholism.

Genetic Relationship Between the Addiction Diagnosis in Adults and Their Childhood Measure of Addiction Liability

Transmissible liability index (TLI), developed employing a high-risk design and item response theory, enables quantification of the latent trait of liability to drug use disorders (DUD) in children. TLI has been shown to have high heritability and predict DUD in young adulthood. This study extends prior research and determines the genetic contribution of DUD liability measured by TLI to adult liability as indexed by DUD diagnosis. The study utilizes data from a twin sample tracked from age 11 to age 25. In addition to confirming TLI’s high heritability and predictive validity, it shows that the genetic component of variance in TLI assessed in childhood accounts for over half of the genetic variance in DUD diagnosis and the entire phenotypic relationship between the two liability measures. This validates TLI as an early measure of DUD liability and supports its utility in early-age genetic and other mechanistic studies of DUD.

Are Alcohol Trajectories a Useful Way of Identifying At-Risk Youth? A Multiwave Longitudinal-Epidemiologic Study

OBJECTIVE Trajectory approaches are a popular way of identifying subgroups of children and adolescents at high risk for developing alcohol use problems. However, mounting evidence challenges the meaning and utility of these putatively discrete alcohol trajectories, which can be analytically derived even in the absence of real subgroups. This study tests the hypothesis that alcohol trajectories may not reflect discrete groups-that the development of alcohol use is continuous rather than categorical. METHOD A multiwave longitudinal-epidemiologic twin study was conducted using 3,762 twins (1,808 male and 1,954 female) aged 11 to 29 years from the Minnesota Center for Twin and Family Research (MCTFR). The main outcome measures included various assessments of substance use, psychopathology, personality, and cognitive ability. RESULTS Although multiple trajectories are derived from growth mixture modeling techniques, these trajectories are arrayed in a tiered spectrum of severity, from lower levels of use to higher levels of use. Trajectories show perfect rank-order stability throughout development, monotonic increases in heritability, and perfect rank-order correlations with established correlates of alcohol use, including other substance use behaviors, psychiatric disorders, personality traits, intelligence, and achievement. CONCLUSION Alcohol trajectories may represent continuous gradations rather than qualitatively distinct subgroups. If so, early detection and interventions for youth based on trajectory subtyping will be less useful than continuous liability assessments. Furthermore, a continuous account of development counters the notion that individuals are predestined to follow one of a few categorically distinct pathways and promotes the opposite idea-that development is mutable, and its continuous terrain can be traversed in many directions.