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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence.

BACKGROUND: Among adolescents, externalizing problem behavior and substance use disorders are often comorbid. Familial influences, including shared genetic risk factors, may account for part of this comorbidity. Previously we reported 2 chromosomal regions (3q24-3q25 and 9q34) likely to contain genes that influence substance dependence vulnerability (DV) in adolescence. OBJECTIVES: To identify quantitative trait loci (QTLs) that influence externalizing problem behavior in adolescence and to determine whether any identified QTL overlap chromosomal regions that influence DV. DESIGN: Regression-based QTL mapping procedures designed for selected sibling pair samples. SETTING: Patient probands were drawn from consecutive admissions to residential and outpatient (milieu-type) treatment facilities for substance abuse and delinquency operated by the University of Colorado; most of these patients were referred for treatment by juvenile justice or social service agencies. PATIENTS: A total of 249 proband-sibling pairs from 191 families were selected for the study. Patient probands were 13 to 19 years of age; siblings of the probands ranged in age from 12 to 25 years. MAIN OUTCOME MEASURES: A community-based sample of 4493 adolescents and young adults was used to define clinically significant, heritable, age- and sex-normed indexes of DV, conduct disorder symptoms (CDS), and a composite index of antisocial substance dependence (DV + CDS). Siblings and parents were genotyped for 374 microsatellite markers distributed across the 22 autosomes (mean intermarker distance, 9.2 centimorgans). RESULTS: For both DV and CDS, there was evidence of linkage to the same region on chromosome 9q34, as well as to 3q24-3q25 for DV, and a novel region on chromosome 17q12 for CDS. Our composite index (DV + CDS) yielded the strongest evidence for linkage (logarithm of odds = 2.65) to the chromosome 9q34 region. CONCLUSION: These results provide the first evidence of a potential molecular genetic basis for the comorbidity between DV and antisocial behavior.

An association between the DAT1 polymorphism and smoking behavior in young adults from the National Longitudinal Study of Adolescent Health.

Associations between smoking behavior and polymorphisms in the dopaminergic genes (DAT1 and DRD2) were tested by using within- and between-family measures of allelic transmission in 2,448 young adults from the National Longitudinal Study of Adolescent Health. The 9-repeat allele of the dopamine transporter gene polymorphism (DAT1) was inversely associated with smoking in samples that included all subjects and only those who had initiated smoking, accounting for approximately 1% of the variance. Never smokers and current nonsmokers had an excess transmission of the 9-repeat allele compared with regular smokers, suggesting a protective effect of the 9-repeat allele, which is hypothesized to alter synaptic dopamine levels.

The family transmission of adolescent alcohol abuse and dependence.

OBJECTIVE: This study examines the familial transmission of alcohol abuse and dependence to adolescents. METHOD: Male adolescents recruited from a treatment program for substance problems, matched controls, and all available biological parents and siblings were assessed with a structured psychiatric interview assessing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, based diagnoses of alcohol abuse and alcohol dependence. A total of 2,612 individuals from 911 families were interviewed. Structural equation modeling estimated tetrachoric correlations among family members, the proportion of variance in abuse and dependence attributable to parent-offspring transmission, and the effects of assortative mating and horizontal transmission among siblings. RESULTS: Tetrachoric correlations among siblings and parent-offspring ranged from .19 to .34 for abuse and dependence. Mother-father correlations were .14 and .37 for abuse and dependence, respectively. Modeling of familial transmission showed that 33% of the variance in abuse and 56% of the variance in dependence was accounted for by factors transmitted from parents. The effects of assortative mating could not be dropped from the abuse model without significant loss of model fit but could be dropped from the dependence model. Horizontal transmission among siblings could be dropped from both models without significant loss of fit. CONCLUSIONS: These results suggest that aggregation of alcohol abuse and alcohol dependence in families of male probands is significantly influenced by parental transmission of risk but is not reliably influenced by horizontal sibling effects such as sibling interactions or cohort effects. Spousal resemblance was found to be an important source of familial aggregation for alcohol abuse but not alcohol dependence.

Genetic influences on quantity of alcohol consumed by adolescents and young adults.

OBJECTIVE: To examine genetic and environmental influences on drinking in a nationally representative study of genetically informative adolescents followed into young adulthood. METHOD: The average quantity of alcohol used per drinking episode during the past year was analyzed in 4432 youth assessed during adolescence (mean age of 16) and then 1 and 6 years later. The variance of quantity of alcohol consumed was decomposed into three components: additive genetic (a2), shared environmental (c2), non-shared environmental (e2). Four candidate genes were tested for association. RESULTS: Wave 1 a2-0.52e2-0.48, Wave 2 a2-0.28e2-0.72, Wave 3 a2-0.30e2-0.70. Genetic correlations between Waves 1 and 2 were 0.85, Waves 1 and 3 were 0.34. The DAT1 440 allele was associated at Wave 1 (p=0.007). DRD2 TaqI A1/A2 was associated at Wave 3 (p=0.007). DRD4 and 5HTT were not associated. The DAT1 and DRD2 polymorphisms accounted for 3.1% and 2.0% of the variation, respectively. CONCLUSION: Genetic influence on drinking behavior was common in adolescents longitudinally assessed 1 year apart, but was less correlated between these adolescents and their assessment as young adults at a subsequent time point. Polymorphisms in genes of the dopaminergic system appear to influence variation in drinking behavior.

A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence.

This study describes results from a genome-wide search for quantitative trait loci (QTL) influencing substance dependence vulnerability in adolescence. We utilized regression-based multipoint (and single-point) QTL mapping procedures designed for selected sibpair samples. Selected sibling pairs included 250 proband-sibling pairs from 192 families. Clinical probands (13-19 years of age) were drawn from consecutive admissions to substance abuse treatment facilities in the Denver metropolitan area; siblings of probands ranged in age from 12 to 25 years. In addition to the selected sample, a community-based sample of 3676 adolescents and young adults were utilized to define a clinically-significant, heritable, age- and sex-normed index of substance dependence vulnerability-a priori and independent of our linkage results. Siblings and their parents were genotyped for 374 STR micro-satellite markers distributed across the 22 autosomes (average inter-marker distance=9.2 cM). Non-parametric single-point linkage results indicated 17 markers on 11 chromosomes with nominally significant tests of linkage; six markers with LOD scores greater than 1.0 and one marker (D3S1614) with a LOD score of 2.2. Multipoint mapping corroborated two locations and provided preliminary evidence for linkage to regions on chromosome 3q24-25 (near markers D3S1279 and D3S1614) and chromosome 9q34 (near markers D9S1826 and D9S1838).

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.

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 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.