Genetic and environmental influences on executive functions and intelligence in middle childhood.

Executive functions (EFs) and intelligence (IQ) are phenotypically correlated. In twin studies, latent variables for EFs and IQ display moderate to high heritability estimates; however, they show variable genetic correlations in twin studies spanning childhood to middle age. We analyzed data from over 11,000 children (9- to 10-year-olds, including 749 twin pairs) in the Adolescent Brain Cognitive Development (ABCD) Study to examine the phenotypic and genetic relations between EFs and IQ in childhood. We identified two EF factors-Common EF and Updating-Specific-which were both related to IQ (rs = 0.64-0.81). Common EF and IQ were heritable (53%-67%), and their genetic correlation (rG = 0.86) was not significantly different than 1. These results suggest that EFs and IQ are phenotypically but not genetically separable in middle childhood, meaning that this phenotypic separability may be influenced by environmental factors.

Screen time and early adolescent mental health, academic, and social outcomes in 9- and 10- year old children: Utilizing the Adolescent Brain Cognitive Development ℠(ABCD) Study.

In a technology-driven society, screens are being used more than ever. The high rate of electronic media use among children and adolescents begs the question: is screen time harming our youth? The current study draws from a nationwide sample of 11,875 participants in the United States, aged 9 to 10 years, from the Adolescent Brain Cognitive Development Study (ABCD Study®). We investigate relationships between screen time and mental health, behavioral problems, academic performance, sleep habits, and peer relationships by conducting a series of correlation and regression analyses, controlling for SES and race/ethnicity. We find that more screen time is moderately associated with worse mental health, increased behavioral problems, decreased academic performance, and poorer sleep, but heightened quality of peer relationships. However, effect sizes associated with screen time and the various outcomes were modest; SES was more strongly associated with each outcome measure. Our analyses do not establish causality and the small effect sizes observed suggest that increased screen time is unlikely to be directly harmful to 9-and-10-year-old children.

Investigating the causal effect of cannabis use on cognitive function with a quasi-experimental co-twin design.

BACKGROUND: It is unclear whether cannabis use causes cognitive decline; several studies show an association between cannabis use and cognitive decline, but quasi-experimental twin studies have found little support for a causal effect. Here, we evaluate the association of cannabis use with general cognitive ability and executive functions (EFs) while controlling for genetic and shared environmental confounds in a longitudinal twin study. METHODS: We first examined the phenotypic associations between cannabis initiation, frequency, and use disorder with cognitive abilities, while also controlling for pre-use general cognitive ability and other substance involvement. We tested the concurrent association between the cannabis use variables and cognitive abilities in late adolescence and young adulthood and the longitudinal association between cannabis use variables during adolescence and young adulthood cognitive abilities. Next, we used multilevel models to test whether these relations reflect between- and/or within-twin pair associations. RESULTS: Phenotypically, cannabis use was related to poorer cognitive functioning, although most associations were negligible after accounting for other substance use. Nevertheless, there were few significant within-family twin-specific associations, except that age 17 cannabis frequency was associated with worse age 23 Common EF and general cognitive ability. CONCLUSIONS: We found little support for a potential causal effect of cannabis use on cognition, consistent with previous twin studies. Results suggest that cannabis use may not cause decline in cognitive ability among a normative sample of cannabis users.

The role of genetic and environmental influences on the association between childhood ADHD symptoms and BMI.

BACKGROUND/OBJECTIVES: Although childhood attention deficit hyperactivity disorder (ADHD) has been previously associated with concurrent and later obesity in adulthood, the etiology of this association remains unclear. The objective of this study is to determine the shared genetic effects of ADHD symptoms and BMI in a large sample of sibling pairs, consider how these shared effects may vary over time, and examine potential sex differences. SUBJECT/METHODS: Sibling pair data were obtained from the National Longitudinal Study of Adolescent to Adult Health (Add Health); childhood ADHD symptoms were reported retrospectively during young adulthood, while three prospective measurements of BMI were available from young adulthood to later adulthood. Cholesky decomposition models were fit to this data using Mx and maximum-likelihood estimation. The twin and sibling sample for these analyses included: 221 monozygotic (MZ) pairs (92 male-male, 139 female-female), 228 dizygotic (DZ) pairs (123 male-male, 105 female-female), 471 full-sibling (FS) pairs (289 male-male, 182 female-female), 106 male-female DZ twin pairs, and 234 male-female FS pairs. RESULTS: The magnitude of the association between childhood ADHD symptoms and BMI changed over time and by sex. The etiological relationship between childhood ADHD symptoms and the three prospective measurements of BMI differed for males and females, such that unique or non-shared environmental influences contributed to the relationship within males and genetic factors contributed to the relationship within females. Specifically, among females, genetic influences on childhood ADHD symptoms were partially shared with those effecting BMI and increased from adolescence to later adulthood (genetic correlation = 0.20 (95% CI: 0.07-0.36) in adolescence and 0.24 (95% CI: 0.10, 0.41) in adulthood). CONCLUSION: Genetic influences on ADHD symptoms in childhood are partially shared with those effecting obesity. However, future research is needed to determine why this association is limited to females.

Simple sequence repeats in the national longitudinal study of adolescent health: an ethnically diverse resource for genetic analysis of health and behavior.

Simple sequence repeats (SSRs) are one of the earliest available forms of genetic variation available for analysis and have been utilized in studies of neurological, behavioral, and health phenotypes. Although findings from these studies have been suggestive, their interpretation has been complicated by a variety of factors including, among others, limited power due to small sample sizes. The current report details the availability, diversity, and allele and genotype frequencies of six commonly examined SSRs in the ethnically diverse, population-based National Longitudinal Study of Adolescent Health. A total of 106,743 genotypes were generated across 15,140 participants that included four microsatellites and two di-nucleotide repeats in three dopamine genes (DAT1, DRD4, DRD5), the serotonin transporter, and monoamine oxidase A. Allele and genotype frequencies showed a complex pattern and differed significantly between populations. For both di-nucleotide repeats we observed a greater allelic diversity than previously reported. The availability of these six SSRs in a large, ethnically diverse sample with extensive environmental measures assessed longitudinally offers a unique resource for researchers interested in health and behavior.

Prevalence and correlates of alcohol and cannabis use disorders in the United States: results from the national longitudinal study of adolescent health.

BACKGROUND: Limited current information on the epidemiology of lifetime alcohol and cannabis use disorders in the United States is available. AIMS: To present detailed information about the prevalence and sociodemographic correlates of lifetime alcohol and cannabis use disorders rates in the United States. To examine gender differences in hazard ratios for the onset of alcohol and cannabis dependence. METHODS: Participants in Wave IV of the National Longitudinal Study of Adolescent Health (N=15,500, age range: 24-32) were interviewed between 2008 and 2009. Participants who exceeded screening thresholds were queried about lifetime DSM-IV alcohol and marijuana abuse and dependence symptoms. Age of substance dependence onset was queried. RESULTS: Lifetime rates of alcohol abuse and dependence were 11.8 and 13.2%. Lifetime rates of cannabis abuse and dependence were 3.9 and 8.3%. Lifetime alcohol and cannabis dependence onset peaks were 23 and 20. Correlates of lifetime alcohol abuse included being male (OR 1.4), African-American (OR 0.7), income in the 2nd or 3rd quartile (OR 0.7 and 0.6). Correlates of lifetime alcohol dependence were: being male (OR 1.8), African-American (OR 0.5), and never being married (OR 1.5), and regions outside of the west (Midwest OR 0.7, South OR 0.6, Northeast OR 0.6). Correlates of cannabis abuse and dependence were being male (OR 1.8 and 1.4). CONCLUSIONS: Lifetime alcohol and cannabis use disorders are highly prevalent in the US population. Men are at higher risk for alcohol and cannabis use disorders. Alcohol use disorders demonstrated specific sociodemographic correlates while marijuana use disorders did not.

MAOA genotype, childhood maltreatment, and their interaction in the etiology of adult antisocial behaviors.

BACKGROUND: Maltreatment by an adult or caregiver during childhood is a prevalent and important predictor of antisocial behaviors in adulthood. A functional promoter polymorphism in the monoamine oxidase A (MAOA) gene has been implicated as a moderating factor in the relationship between childhood maltreatment and antisocial behaviors. Although there have been numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this gene-environment interaction hypothesis in a sample of 3356 white and 960 black men (aged 24-34) participating in the National Longitudinal Study of Adolescent Health. RESULTS: Primary analysis indicated that childhood maltreatment was a significant risk factor for later behaviors that violate rules and the rights of others (p < .05), there were no main effects of MAOA genotype, and MAOA genotype was not a significant moderator of the relationship between maltreatment and antisocial behaviors in our white sample. Post hoc analyses identified a similar pattern of results among our black sample in which maltreatment was not a significant predictor of antisocial behavior. Post hoc analyses also revealed a main effect of MAOA genotype on having a disposition toward violence in both samples and for violent convictions among our black sample. None of these post hoc findings, however, survived correction for multiple testing (p > .05). Power analyses indicated that these results were not due to insufficient statistical power. CONCLUSIONS: We could not confirm the hypothesis that MAOA genotype moderates the relationship between childhood maltreatment and adult antisocial behaviors.

The CHRNA5/A3/B4 gene cluster and tobacco, alcohol, cannabis, inhalants and other substance use initiation: replication and new findings using mixture analyses.

Multiple studies have provided evidence for genetic associations between single nucleotide polymorphisms (SNPs) located on the CHRNA5/A3/B4 gene cluster and various phenotypes related to Nicotine Dependence (Greenbaum et al. 2009). Only a few studies have investigated other substances of abuse. The current study has two aims, (1) to extend previous findings by focusing on associations between the CHRNA5/A3/B4 gene cluster and age of initiation of several different substances, and (2) to investigate heterogeneity in age of initiation across the different substances. All analyses were conducted with a subset of the Add Health study with available genetic data. The first aim was met by modeling onset of tobacco, alcohol, cannabis, inhalants, and other substance use using survival mixture analysis (SMA). Ten SNPs in CHRNA5/A3/B4 were used to predict phenotypic differences in the risk of onset, and differences between users and non-users. The survival models aim at investigating differences in the risk of initiation across the 5-18 age range for each phenotype separately. Significant or marginally significant genetic effects were found for all phenotypes. The genetic effects were mainly related to the risk of initiation and to a lesser extent to discriminating between users and non-users. To address the second goal, the survival analyses were complemented by a latent class analysis that modeled all phenotypes jointly. One of the ten SNPs was found to predict differences between the early and late onset classes. Taken together, our study provides evidence for a general role of the CHRNA5/A3/B4 gene cluster in substance use initiation that is not limited to nicotine and alcohol.

Dizziness and the genetic influences on subjective experiences to initial cigarette use.

AIM: To examine individual differences in positive and negative subjective experiences to initial cigarette use. DESIGN: Retrospective self-reports of initial subjective experiences were examined to estimate the genetic and environmental influences and the extent of their covariation across different effects. PARTICIPANTS: Data was drawn from 2482 young adult same-and opposite sex twins- and siblings participating in the National Longitudinal Study of Adolescent Health. MEASUREMENT: Subjective experiences were retrospectively collected using the Early Smoking Experience (ESE) questionnaire. FINDINGS: Positive experiences evidenced moderate heritable contributions (40%, 95% CI: 0.22 to 0.56), as did an overall hedonic measure (34%, 95% CI: 0.22 to 0.46) and dizziness (34%, 95% CI: 0.15 to 0.52). Negative experiences evidenced small heritable contributions (13%, 95% CI: 0.00 to 0.36). Individual specific environmental influences were strong and accounted for the remaining proportion of observed variation in these experiences. Multivariate genetic modeling identified a moderately heritable underlying factor (37%, 95% CI: 0.22 to 0.52) that influenced the covariation of diverse subjective experiences and loaded most heavily on dizziness. Positive experiences also evidence residual genetic influences that were uncorrelated with other subjective experiences. CONCLUSIONS: How a person experiences their initial few cigarettes is due to both heritable contributions and environmental experiences unique to the person. The covariation of diverse subjective experiences appears to be due to a heritable latent sensitivity to the chemicals contained in an average cigarette and is best indexed by dizziness.

The association between conduct problems and maltreatment: testing genetic and environmental mediation.

It is often assumed that childhood maltreatment causes conduct problems via an environmentally mediated process. However, the association may be due alternatively to either a nonpassive gene-environment correlation, in which parents react to children's genetically-influenced conduct problems by maltreating them, or a passive gene-environment correlation, in which parents' tendency to engage in maltreatment and children's conduct problems are both influenced by a hereditary vulnerability to antisocial behavior (i.e. genetic mediation). The present study estimated the contribution of these processes to the association between maltreatment and conduct problems. Bivariate behavior genetic analyses were conducted on approximately 1,650 twin and sibling pairs drawn from a large longitudinal study of adolescent health (Add Health). The correlation between maltreatment and conduct problems was small; much of the association between maltreatment and conduct problems was due to a nonpassive gene-environment correlation. Results were more consistent with the hypothesis that parents respond to children's genetically-influenced conduct problems by maltreating them than the hypothesis that maltreatment causes conduct problems.

Investigation of genetically mediated child effects on maltreatment.

Theory and empirical evidence suggest that children's genetically influenced characteristics help to shape the environments they experience, including the parenting they 'receive'. The extent of these genetically-mediated child effects on childhood maltreatment is not well known. The present study estimates the magnitude of genetically mediated child effects on maltreatment in 3,297 twins and siblings who were part of a large nationally representative sample of adolescents (ADD health). Participants in early adulthood retrospectively reported their experiences of physical and sexual maltreatment and neglect. Results are consistent with small genetically-mediated child effects on physical maltreatment and neglect, and none on sexual maltreatment, and all three forms of maltreatment are influenced mainly by idiosyncratic individual circumstances.

Association of candidate genes with antisocial drug dependence in adolescents.

The Colorado Center For Antisocial Drug Dependence (CADD) is using several research designs and strategies in its study of the genetic basis for antisocial drug dependence in adolescents. This study reports single nucleotide polymorphism (SNP) association results from a targeted gene assay (SNP chip) of 231 primarily Caucasian male probands in treatment with antisocial drug dependence and a matched set of community controls. The SNP chip was designed to assay 1500 SNPs distributed across 50 candidate genes that have had associations with substance use disorders and conduct disorder. There was an average gene-wide inter-SNP interval of 3000 base pairs. After eliminating SNPs with poor signals and low minor allele frequencies, 60 nominally significant associations were found among the remaining 1073 SNPs in 18 of 49 candidate genes. Although none of the SNPs achieved genome-wide association significance levels (defined as p<.000001), two genes probed with multiple SNPs (OPRM1 and CHRNA2) emerged as plausible candidates for a role in antisocial drug dependence after gene-based permutation tests. The custom-designed SNP chip served as an effective and flexible platform for rapid interrogation of a large number of plausible candidate genes.

The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults.

BACKGROUND: One potential site of convergence of the nicotine and alcohol actions is the family of the neuronal nicotinic acetylcholine receptors. Our study examines the genetic association between variations in the genomic region containing the CHRNA5, A3, and B4 gene cluster (A5A3B4) and several phenotypes of alcohol and tobacco use in an ethnically diverse young adult sample. Significant results were then replicated in a separate adult population-representative sample. METHODS: In a selected sample, nine single nucleotide polymorphisms (SNPs) were tested for association with various nicotine and alcohol phenotypes, including age of initiation and measures of frequency, quantity, and subjective responses to the substances. Analysis was conducted with the statistical genetics program WHAP in the full sample (1075 subjects) including ethnicities as covariates and within each ethnic group sub-sample. Replication of the significant results in a separate population-based sample was carried out with the PBAT statistical genetics program. RESULTS: Two linked SNPs (rs8023462 and rs1948) located in a conserved region of the A5A3B4 gene cluster significantly predicted early age of initiation for tobacco with a hazard ratio (HR) of 1.35 (95% confidence interval [CI]1.08-1.70) for the CC genotype of rs8023462 and a HR of 1.29 (95% CI 1.01-1.63) for the TT genotype of rs1948 [corrected]. These findings were then replicated in a separate population-representative sample, showing rs1948 and rs8023462 to be associated with age of initiation for both tobacco and alcohol use (p < .01 and p < .001). CONCLUSIONS: Variations in A5A3B4 genes might influence behaviors that promote early age of experimentation with drugs.

The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco.

Neuronal nicotinic acetylcholine receptors have been implicated in various measures of nicotine dependence. In this paper, we present findings from an exploratory study of single nucleotide polymorphisms (SNPs) in the CHRNB3 and CHRNA6 genes with tobacco and alcohol phenotypes, including frequency of use and three subjective response factors occurring shortly after initiation of use. Subjects were 1056 ethnically diverse adolescents ascertained from clinical and community settings. The most significant associations were found between two CHRNB3 SNPs (rs4950 and rs13280604) and the three subjective response factors to initial tobacco use. These findings were replicated in a separate community sample of 1524 families participating in the National Longitudinal Study of Adolescent Health. Both CHRNB3 SNPs were found to be associated with similar measures of subjective response to tobacco. These results indicate that early subjective response to nicotine may be a valuable endophenotype for genetic studies aimed at uncovering genes contributing to nicotine use and addiction.

The human protein kinase C gamma gene (PRKCG) as a susceptibility locus for behavioral disinhibition.

This study explores the association between a highly heritable behavioral disinhibition phenotype and the protein kinase C gamma (PRKCG) gene in an ethnically diverse youth sample from Colorado, USA. The rationale for this study was based on the impulsive behavior and increased ethanol consumption observed in the protein kinase C gamma (PKC-gamma)-deficient mouse model. Two composite behavioral disinhibition phenotypes and their component behavioral scores [conduct disorder, attention-deficit hyperactivity disorder (ADHD), substance experimentation (SUB) and novelty-seeking] were examined for association with five independent PRKCG single nucleotide polymorphisms (SNPs). Association analysis for the five individual SNPs revealed modest genetic association of Exon 14 (rs2242244) and Upstream (rs307941) markers with the behavioral disinhibition composite variables in the combined, Hispanic and African-American samples. Additionally, haplotype-based association analysis for two SNPs located in Intron 3 (rs402691) and Exon 6 (rs3745406) indicated a significant overall association of the PRKCG locus with the ADHD-hyperactive subscale scores in the combined and Caucasian samples, supporting the relation between impulsive behaviors and the PRKCG gene. A significant haplotype association was also observed with SUB scores but only in the Hispanic ethnic group, highlighting the marker variability for each ethnic group. In conclusion, our results support the role of the PKC-gamma enzyme in behavioral impulsivity previously observed in mice. This study provides the first exploration of the PRKCG gene and its association with behavioral disinhibition and warrants further study in other larger population samples.

College attendance and its effect on drinking behaviors in a longitudinal study of adolescents.

BACKGROUND: While college attendance has been shown to be associated with increased drinking behaviors, there are no studies to our knowledge that have examined whether college attendance moderates genetic influences for drinking. We first tested for changes in alcohol consumption in adolescents who did and did not subsequently attend college, and then tested for variation of the genetic and environmental determinants of drinking in these 2 groups. METHODS: Participants eligible for this study were selected from 2 samples from the National Longitudinal Study of Adolescent Health (Add Health), a national probability sample (n=7,083) and a sample of sibling pairs (n=855 pairs). Participants were assessed for measures of drinking behaviors as adolescents (wave I) and reinterviewed at 1 (wave II) and 6 years (wave III) following the initial survey. Changes in binge drinking and average quantity of alcohol consumed in the past year were estimated among 4 groups (2-year college students, 4-year college students, college withdrawers, noncollege participants) in sequential cohorts which spanned the ages of 13 to 24 across the 3 Add Health waves. Gene by environment interactions were then tested at wave III using biometrical models in the genetically informative pairs. RESULTS: Participants who did not attend college reported more binge drinking and consumed greater quantities of alcohol as adolescents than participants who subsequently attended college. However, the college students not only surpassed their noncollege peers in alcohol use as young adults, but also exhibited a greater genetic influence on quantity of alcohol consumed per drinking episode. CONCLUSIONS: Exposure to a college environment acts as an environmental moderator, supporting the hypothesis that the magnitude of genetic influence on certain aspects of alcohol consumption is greater in environments where drinking behaviors are more likely to be promoted.

Genes, time to first cigarette and nicotine dependence in a general population sample of young adults.

AIM: To examine variation in nicotine dependence scores and covariation between different dependence symptoms. DESIGN: A 12-year, nationally representative, probability-based survey of adolescent health-related behaviors and their outcomes during young adulthood in the United States. The genetic contribution to nicotine dependence was evaluated in the sibling-pairs sample of the US National Longitudinal Study of Adolescent Health. MEASUREMENTS: Nicotine dependence (ND) was assessed using the Fagerström Test for Nicotine Dependence (FTND) and Heaviness of Smoking Index (HSI) in 1154 young adults, between the ages of 18 and 25 years, who were from twin, full sibling and half-sibling pairs. FINDINGS: Dependence in this sample was common and varied in degree. Total HSI scores evidenced moderate to large heritable contributions (61%, 95% confidence interval (CI): 0.46-0.72), as did the quantity of cigarettes smoked (52%, 95% CI: 0.39-0.63) and urgency to smoke (55%, 95% CI: 0.38-0.68). Multivariate modeling identified a highly heritable underlying factor (76%, 95% CI: 0.56-0.91) that influenced the covariation of dependence symptoms and loaded most heavily on how soon after waking a smoker uses his or her first cigarette. The quantity of cigarettes smoked per day also evidenced residual genetic influences that were not common to other dependence-related behaviors. CONCLUSIONS: In this sample of young adults from the general population, both genes and individual-specific environments are important etiological factors in ND. The urgency to smoke, as measured by the time to first cigarette, may be the most informative measure on the FTND for genetic studies of nicotine dependence.

Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine.

Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples. Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. However, a SNP (rs2072658) located immediately upstream of CHRNB2 was associated with the initial subjective response to both alcohol and tobacco. This study provides the first evidence for association between the CHRNB2 gene and nicotine- and alcohol-related phenotypes, and suggests that polymorphisms in CHRNB2 may be important in mediating early responses to nicotine and alcohol.

A genome-wide scan for loci influencing adolescent cannabis dependence symptoms: evidence for linkage on chromosomes 3 and 9.

OBJECTIVE: Cannabis is the most frequently abused illicit substance among adolescents and young adults. Genetic risk factors account for part of the variation in the development of cannabis dependence symptoms; however, no linkage studies have been performed for cannabis dependence symptoms. This study aimed to identify such loci. METHOD: Three hundred and twenty-four sibling pairs from 192 families were assessed for cannabis dependence symptoms. Probands (13-19 years of age) were recruited from consecutive admissions to substance abuse treatment facilities. The siblings of the probands ranged in age from 12 to 25 years. A community-based sample of 4843 adolescents and young adults was utilized to define an age- and sex-corrected index of cannabis dependence vulnerability. DSM-IV cannabis dependence symptoms were assessed in youth and their family members with the Composite International Diagnostic Instrument-Substance Abuse Module. Siblings and parents were genotyped for 374 microsatellite markers distributed across the 22 autosomes (average inter-marker distance=9.2cM). Cannabis dependence symptoms were analyzed using Merlin-regress, a regression-based method that is robust to sample selection. RESULTS: Evidence for suggestive linkage was found on chromosome 3q21 near marker D3S1267 (LOD=2.61), and on chromosome 9q34 near marker D9S1826 (LOD=2.57). CONCLUSIONS: This is the first reported linkage study of cannabis dependence symptoms. Other reports of linkage regions for illicit substance dependence have been reported near 3q21, suggesting that this region may contain a quantitative trait loci influencing cannabis dependence and other substance use disorders.

Progression from marijuana use to daily smoking and nicotine dependence in a national sample of U.S. adolescents.

BACKGROUND: While it has been demonstrated that smoking cigarettes in adolescence increases the likelihood of progressing to marijuana use, few studies have considered the reverse scenario in which early use of cannabis leads to greater tobacco smoking. METHODS: Participants (n=5963), who had never smoked cigarettes daily by wave I of the National Longitudinal Study of Adolescent Health, were followed 6 years (waves I-III) from adolescence into young adulthood. Measures of marijuana use (lifetime use, monthly use, age at first use), as assessed at wave I within 12-16 (n=3712) and 17-21 (n=2251) year-olds, were separately modeled as predictors of three tobacco-related outcomes: (1) age at onset of daily cigarette smoking, (2) lifetime nicotine dependence, (3) current nicotine dependence. RESULTS: In the older cohort (17-21-year-olds at wave I), lifetime (>10 times) and past-month marijuana use at wave I were predictive of an earlier initiation into daily cigarette smoking and a greater likelihood of developing nicotine dependence by wave III. Furthermore, age at first use of cannabis was negatively associated with risk of nicotine dependence in the older, but not younger cohort. CONCLUSION: After controlling for baseline measures of tobacco smoking and other demographic risk factors, the use of marijuana in adolescence was modestly associated with daily cigarette smoking and nicotine dependence in young adulthood.