Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster.

There is strong evidence for shared genetic factors contributing to childhood externalizing disorders and substance abuse. Externalizing disorders often precede early substance experimentation, leading to the idea that individuals inherit a genetic vulnerability to generalized disinhibitory psychopathology. Genetic variation in the CHRNA5/CHRNA3/CHRNB4 gene cluster has been associated with early substance experimentation, nicotine dependence, and other drug behaviors. This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples. We developed a common externalizing behavior phenotype from the available measures in the three samples, and tested for association with 10 SNPs in the gene cluster. Significant results were detected in two of the samples, including rs8040868, which remained significant after controlling for smoking quantity. These results expand on previous work focused mainly on drug behaviors, and support the hypothesis that variation in the CHRNA5/CHRNA3/CHRNB4 locus is associated with early externalizing behaviors.

The effects of cannabis use on physical health: A co-twin control study.

BACKGROUND: Research on the influence of cannabis use on anthropometrics, cardiovascular and pulmonary function, and other indicators of physical health has reported mixed results. We examined whether cannabis frequency is associated with physical health outcomes phenotypically and after controlling for shared genetic and environmental factors via a longitudinal co-twin control design. METHODS: We tested the phenotypic associations of adolescent, young adult, and adult cannabis frequency with adult physical health. Next, we ran multilevel models to test if significant phenotypic associations remained at the between-family and within-twin pair levels. Participants include 677 individual twins (308 twin pairs) aged 25-35. RESULTS: At the phenotypic level, adolescent cannabis use was associated with less adult exercise engagement (b = - 0.846 min, p = .000). Adult cannabis use was associated with a lower resting heart rate (HR; b = - 0.170 bpm, p = .001) and more frequent appetite loss (b = 0.018, p = .000). Only between-family effects were significant for adolescent cannabis use and exercise engagement (b = - 1.147 min, p = .000) and adult cannabis use and appetite loss frequency (b = 0.041, p = .002). The total within-twin (b = - 0.184, p = .014), MZ only (b = - 0.304, p = .003), and between-family effects (b = - 0.164, p = .025) were significant between adult cannabis use and a lower resting HR, which persisted after controlling for familial confounds and other substance use. CONCLUSIONS: The associations between cannabis use with exercise engagement and frequency of appetite loss are explained by familial confounding while the association between cannabis use and resting HR was not. These results do not support a causal association between cannabis use once a week and poorer physical health effects among adults aged 25-35.

Early childhood temperament and the covariation between internalizing and externalizing behavior in school-aged children.

There is significant covariation between internalizing and externalizing behavior, although there is also evidence that internalizing behavior is a protective factor against externalizing behavior. Several researchers have posited that the examination of the relationship between temperament or personality and behavior problems may help explain these seemingly contradictory results. Specifically, negative emotionality or neuroticism has been cited as a temperament characteristic that internalizing and externalizing behavior share in common, whereas behavioral inhibition may be related only to internalizing behavior. We examined the degree to which the covariation between internalizing and externalizing behavior assessed from age 4 to 12 years can be explained by temperament characteristics assessed from age 14 to 36 months. Additionally, we assessed the extent to which this relationship is due to genetic or environmental factors, analyzing data from 225 monozygotic and 185 dizygotic twin pairs assessed by the Colorado Longitudinal Twin Study. In males, a portion of the covariation between internalizing and externalizing behavior was explained by shared environmental influences in common with emotionality and shared environmental influences in common with shyness. In females, most of the covariation between internalizing and externalizing behavior was explained by shared environmental influences in common with emotionality. A possible limitation of this study is that the covariation between temperament and behavior problems may be due to shared measurement variance, as parent ratings were used to assess both temperament and behavior problems.

Prospective effects of adolescent indicators of behavioral disinhibition on DSM-IV alcohol, tobacco, and illicit drug dependence in young adulthood.

OBJECTIVE: To identify robust predictors of drug dependence. METHODS: This longitudinal study included 2361 male and female twins from an ongoing longitudinal study at the Center for Antisocial Drug Dependence (CADD) at the University of Colorado Boulder and Denver campuses. Twins were recruited for the CADD project while they were between the ages of 12 and 18. Participants in the current study were on average approximately 15years of age during the first wave of assessment and approximately 20years of age at the second wave of assessment. The average time between assessments was five years. A structured interview was administered at each assessment to determine patterns of substance use and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; Fourth Edition) attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and drug dependence symptoms. Cloninger's Tridimensional Personality Questionnaire was also used to assess novelty seeking tendencies (NS). At the second wave of assessment, DSM-IV dependence symptoms were reassessed using the same interview. Path analyses were used to examine direct and indirect mechanisms linking psychopathology and drug outcomes. RESULTS: Adolescent substance use, CD, and NS predicted young adult substance dependence, whereas the predictive effects of ADHD were few and inconsistent. Furthermore, CD and NS effects were partially mediated by adolescent substance use. CONCLUSIONS: Adolescent conduct problems, novelty seeking, and drug use are important indices of future drug problems. The strongest predictor was novelty seeking.

Structure and etiology of co-occurring internalizing and externalizing disorders in adolescents.

Several studies suggest that a two-factor model positing internalizing and externalizing factors explains the interrelationships among psychiatric disorders. However, it is unclear whether the covariation between internalizing and externalizing disorders is due to common genetic or environmental influences. We examined whether a model positing two latent factors, internalizing and externalizing, explained the interrelationships among six psychiatric disorders (major depressive disorder, generalized anxiety disorder, separation anxiety disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder) in adolescents, and whether there are common genetic and environmental influences on internalizing and externalizing latent factors. Multivariate behavior genetic analyses of data from 1162 twin pairs and 426 siblings ascertained from the general population via the Colorado Center for Antisocial Drug Dependence (CADD) were conducted. We found support for a model positing two latent factors (internalizing and externalizing). These factors were moderately heritable and influenced by significant common genetic and nonshared environmental influences. These findings suggest that co-occurrence of internalizing and externalizing psychopathology in adolescents results from both genetic and environmental influences.

The inclusion of measured covariates in the Neale and Kendler model fitting approach.

Neale and Kendler (1995, Am J Hum Genet 57:935-953) described 13 comorbidity models, providing the most comprehensive set of alternative hypotheses regarding the possible causes of comorbidity to date. This research note describes an extension of the Neale and Kendler model fitting approach that permits the inclusion of measured covariates. An example of 13 models examining the comorbidity between alcohol dependence and illicit drug dependence is presented.