Genetic and environmental influences on externalizing behavior and alcohol problems in adolescence: A female twin study

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Abstract

Genetic and environmental contributions to the observed correlations among DSM-IV ADHD problems [inattentive (INATT) and hyperactive/impulsive (HYP/IMP) behaviors], conduct problems (CDP) and alcohol problems (AlcProb) were examined by fitting multivariate structural equation models to data from the Missouri Adolescent Female Twin Study [N = 2892 twins (831 monozygotic pairs, 615 dizygotic pairs)]. Based on results of preliminary regression models, we modified the structural model to jointly estimate (i) the regression of each phenotype on significant familial/prenatal predictors, and (ii) genetic and environmental contributions to the residual variance and covariance. Results suggested that (i) parental risk factors, such as parental alcohol dependence and regular smoking, increase risk for externalizing behavior; (ii) prenatal exposures predicted increased symptomatology for HYP/IMP (smoking during pregnancy), INATT and CDP (prenatal alcohol exposure); (iii) after adjusting for measured familial/prenatal risk factors, genetic influences were significant for HYP/IMP, INATT, and CDP; however, similar to earlier reports, genetic effects on alcohol dependence symptoms were negligible; and (iv) in adolescence, correlated liabilities for conduct and alcohol problems are found in environmental factors common to both phenotypes, while covariation among impulsivity, inattention, and conduct problems is primarily due to genetic influences common to these three behaviors. Thus, while a variety of adolescent problem behaviors are significantly correlated, the structure of that association may differ as a function of phenotype (e.g., comorbid HYP/IMP and CDP vs. comorbid CDP and AlcProb), a finding that could inform different approaches to treatment and prevention.

Introduction

The relationship between childhood externalizing or disruptive behavior and substance use and dependence in adulthood has been well established (e.g., Robins, 1966, Robins, 1998, Caspi et al., 1996). Similar relationships have also been reported between childhood disruptive behavior and early alcohol use and alcohol dependence in adolescence (e.g., Disney et al., 1999, Kuperman et al., 2001). In particular, children with attention-deficit hyperactivity disorder (ADHD) appear to be at risk for substance use problems as they reach adolescence and adulthood (Flory et al., 2003). Several mechanisms have been postulated for this apparent association. First, children with ADHD are at risk for alcoholism because of their behavioral profiles in early childhood — profiles that include impulsivity, distractability, hyperactivity and, in general, cognitive and behavioral under-regulation (e.g., Smith et al., 2002). These symptoms not only describe ADHD, but also the larger construct of behavioral undercontrol implicated in alcoholism theory (Molina et al., 2007, Sher, 1991, Tarter et al., 1990, Zucker et al., 1995). Second, the association between ADHD and substance abuse may be merely an artifact of the overlap between ADHD and other behavioral problems, such as conduct disorder (CD) which has been shown, in both clinical and epidemiological samples, to co-occur with ADHD 30–50% (e.g., Szatmari et al., 1989, Biederman et al., 1987). In addition to its comorbidity with ADHD, CD has been implicated as a robust predictor of both concurrent and future alcohol problems (Rose et al., 2004), and evidence suggests that, among all childhood behavioral disorders, CD exhibits the strongest association with alcohol problems (Disney et al., 1999, Greenbaum et al., 1991, Molina et al., 2002, Moss and Lynch, 2001). Third, the co-occurrence of ADHD and CD represents a particularly severe form of CD that increases risk for later, adverse outcomes, such as substance use problems, and disorder (e.g., Disney et al., 1999, Fergusson et al., 1993, Flory et al., 2003, Molina et al., 1999).

In addition to the examination of the more direct observable relationships among these behaviors, there is also active research in the possible roles of familial and environmental factors in the etiology of childhood behavioral problems. For example, substance use problems and disorder in parents, which have been associated with ADHD (e.g., Knopik et al., 2005), can result in a variety of detrimental rearing environments including, but not limited to, poor parenting, lack of parental discipline, and increased family conflict (e.g. Eliason and Skinstad, 1995, Ohannessian et al., 2004), all of which can contribute to child mis-behavior. Additional familial/environmental factors include pre- and perinatal risk factors such as low birth weight, prenatal substance exposure and secondary hand smoke exposure. Very low and low birth weights have been associated with ADHD symptoms in childhood (Botting et al., 1997, Breslau and Chilcoat, 2000, Mick et al., 2002b). Prenatal exposure to alcohol has been reported to be predictive of ADHD in childhood (Knopik et al., 2005, Streissguth et al., 1994, Coles et al., 1997) as well as earlier onset (e.g., Russell, 1991) and increased risk (Alati et al., 2006, Baer et al., 2003) of alcohol problems. Maternal smoking during pregnancy has also been shown to increase risk for ADHD (Knopik et al., 2006, Milberger et al., 1996, Milberger et al., 1998, Mick et al., 2002a) as well as CD (Wakschlag et al., 2002).

Interestingly, despite interest in the phenotypic (or observed) relationship between childhood disruptive behavior and alcohol use, very little work has focused on subtypes of ADHD (i.e., inattention and hyperactivity/impulsivity) or the underlying genetic and environmental structures of the interrelationships among ADHD, CD, and alcohol problems, particularly in adolescence. Specifically, an additional mechanism could account for apparent associations between externalizing behavior and alcohol use in adolescence such that these phenotypes may share common genetic variance (“common genes” hypothesis) whereby comorbidity may be best explained by genes with pleiotropic effects (i.e., genes that influence more than one trait). In support of this “common genes” hypothesis, the covariation between hyperactivity and CD (Silberg et al., 1996) and CD, ADHD, and oppositional-defiant disorder (Dick et al., 2005, Nadder et al., 2002, Waldman et al.) in adolescence was found to be largely attributable to genetic factors, and there is fairly strong evidence that a common genetic factor underlies much of the phenotypic association among alcoholism, drug abuse, antisocial personality and CD in late adolescence and adulthood (Hicks et al., 2004, Krueger et al., 2002, Slutske et al., 1998). However, disorder-specific genetic variance also appears important (Blonigen et al., 2005, Dick et al., 2005, Krueger et al., 2002). On the other hand, genetically informative studies of specific relevance to the covariance between alcohol problems and ADHD are surprisingly limited in spite of ample evidence that genetic influences underlie each disorder (e.g. Knopik et al., 2004, Knopik et al., 2005). For instance, Young et al. (2000) examined ADHD, CD, substance experimentation (including alcohol, nicotine, and illicit drug use) and novelty seeking in adolescents as indices of a latent behavioral disinhibition trait, which was found to be highly heritable. However, the lack of a direct assessment of alcohol and the additional variables contributing to the latent behavioral disinhibition trait make it difficult to extrapolate the magnitude of genetic influences to the covariation among ADHD and alcohol problems. Further, while some evidence for common genes exists, other studies have suggested that environmental influences, rather than genetic, underlie the co-occurrence of disruptive behaviors, particularly ADHD, CD, and oppositional-defiant disorder (Burt et al., 2001, Burt et al., 2005). Additionally, Rose et al. (2004) reported that, at age 14, genetic influences on alcohol dependence were negligible and that the covariation among symptoms of CD and alcohol dependence was due to environmental factors that are common to both phenotypes.

The aims of the present study focus on extending prior work by examining the relationships among ADHD, including Inattentive (INATT) and Hyperactive/Impulsive (HYP/IMP) subtypes, conduct problems (CDP), and alcohol problems (AlcProb) in adolescence and by addressing the following questions: First, are there associations between familial and environmental risk factors (i.e., parental alcoholism, parental smoking, maternal drinking/smoking during pregnancy, low birth weight) and our four defined phenotypes: inattention (INATT), hyperactivity/impulsivity (HYP/IMP), conduct problems (CDP) and alcohol problems (AlcProb) in adolescence? Second, after adjusting for pertinent familial risk factors, what proportion of the residual variance in each of these phenotypes is due to genetic and environmental factors? Finally, after adjusting for measured familial risk, what proportion of the comorbidity among these behavioral patterns is driven by biological risk, environmental risk, or both?

Section snippets

Participants and measures

Data were obtained from the Missouri Adolescent Female Twin Study cohort, a sample of female adolescent twin pairs and their parents participating in a longitudinal study of the development of alcohol problems and associated psychopathology in adolescent girls and women (MOAFTS; Heath et al., 2002). All twin pairs born in Missouri to Missouri-resident parents between July 1, 1975 and June 30, 1985, where both twins were still living, were identified from birth records. A cohort-sequential

Results

Twin pairs ranged in age from 11 to 23 years, with an average of 15.15 years. 4.6% of mothers met criteria for alcohol dependence (AlcD), 8.9% of mothers for alcohol abuse (AlcA), and based on maternal history report, 19.4% of fathers for AlcD. With regard to smoking, 37.1% of mothers and 40.1% of fathers were regular smokers (defined by twin report); moreover, 37% of mothers reported smoking during the 1st trimester and 21% continued to smoke beyond the 1st trimester. 24% of mothers reported

Discussion

This investigation sought to determine the structure of the comorbidity among four adolescent phenotypes indexing externalizing behaviors: hyperactivity/impulsivity, inattention, conduct problems, and alcohol problems. Specifically, we sought to examine measured familial/environmental risk factors and their associations with externalizing behavior and alcohol problems and, once taking those measured risks into account, to determine what proportion of the variance and covariance among these

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    This work supported by NIH grants: DA17671, AA07728, AA09022, AA11998, HD049024.

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