Substance Use/ Abuse

Hicks, B.M., Johnson, W., Durbin, C.E., Blonigen, D.M., Iacono, W.G., & McGue, M. (2013). Gene-environment correlation in the development of adolescent substance abuse: Selection effects of child personality and mediation via contextual risk factors. Development & Psychopathology, 25(2013), 119-132. PMCID: PMC3578304

Abstract: We used a longitudinal twin design to examine selection effects of personality traits at age 11 on high-risk environmental contexts at age 14 and the extent to which these contexts mediated risk for substance abuse at age 17. Socialization at age 11 (willingness to follow rules and endorse conventional values) predicted exposure to contextual risk at age 14. Contextual risk partially mediated the effect of socialization on substance abuse, though socialization also had a direct effect. In contrast, boldness at age 11 (social engagement and assurance, thrill seeking, and stress resilience) also predicted substance abuse directly but was unrelated to contextual risk. There was substantial overlap in the genetic and shared environmental influences on socialization and contextual risk, and genetic risk in socialization contributed to substance abuse indirectly via increased exposure to contextual risk. This suggests that active gene-environment correlations related to individual differences in socialization contributed to an early, high-risk developmental trajectory for adolescent substance abuse. In contrast, boldness appeared to index an independent and direct genetic risk factor for adolescent substance abuse.

Marmorstein, N., Iacono, W., McGue, M. (2012). Associations between substance use disorders and major depression in parents and late adolescent-emerging adult offspring: an adoption study. Addiction, 107, 1965-1973. PMCID: PMC3431451

Findings: (1) when the same disorder in parents and adolescents was examined, parental MDD was associated with increased risk for MDD among both adopted (p<.001) and non-adopted (p<.01) adolescents; in contrast, SUDs were associated with increased risk for the same SUD in non-adopted offspring (all p<.01). (2) When cross-SUD effects were examined, for the most part, each SUD was associated with increased risk for other SUDs among non-adopted but not adopted offspring (most p<.05). (3) When MDD-SUD associations were examined, parental ND and CUDs predicted increased risk for MDD in non-adopted (p<.001), but not adopted, adolescents. These effects tended to remain significant when adjusting for within-person comorbidity (p<.05).
Conclusions: Major depressive disorder in parents appears to be a risk factor for late adolescent-emerging adult major depressive disorder but not substance use disorder in offspring, with this risk being environmentally mediated. Substance use disorder in parents appears, via genetic mediation, to increase risk of substance use disorder in adolescent offspring, and cannabis and nicotine use disorders in parents similarly contribute to major depressive disorder in those offspring.

Elkins, I.J., King, S.M., McGue, M. & Iacono, W.G. (2006) Personality Traits and the Development of Nicotine, Alcohol, and Illicit Drug Disorders: Prospective Links from Adolescence to Young Adulthood. Journal of Abnormal Psychology, 115, 26-39.
The personality traits constraint (CN) and negative emotionality (NE) have been more (CN) or less (NE) consistently associated with alcoholism. The authors examined the association of personality at age 17 with timing of onset and with prospective prediction of nicotine, alcohol, and illicit drug disorders 3 years later in a twin sample (569 females; 432 males). Earlier onset of alcohol and drug disorders (by age 17) was related to significantly lower CN compared with later onsets (by age 20); high NE was related to either onset. NE, as well as CN, uniquely predicted new onsets of all 3 types of substance use disorders by follow-up, with preexisting substance disorders taken into account. Personality traits confer generalized risk for developing any substance disorder, though some traits are more strongly linked with some substance disorders than with others.

Frederick, J.A. & Iacono, W.G. (2006) Beyond the DSM: Defining Endophenotypes for Genetic Studies of Substance Abuse. Current Psychiatry Reports, 8, 144-150.
Although substance-related disorders are heritable, the genetic factors contributing to vulnerability to these disorders are expected to be complex. Nonetheless, identifying genes underlying this vulnerability and understanding their relationship with environmental factors and behavior holds the promise of dramatic advances in diagnosis, prevention, and treatment. The search is complicated by a number of factors, however, including the weak validity of psychiatric diagnosis for identifying gene carriers, the complexity of the brain and behavior, and the numerous intervening variables between genetic transcription and its behavioral consequences. One strategy for bridging this theoretical gap is to study endophenotypes—biologic correlates of disorders that precede their overt development, may have higher reliability than behavioral measures, and present simpler relationships with a smaller number of genes. This article reviews research suggesting the usefulness of several putative endophenotypes for substance-related disorders, including 1) reduced P3 amplitude of the visual event-related
potential, 2) increased EEG beta power, 3) a lowered level of response to an alcohol challenge, and 4) the inability to modulate autonomic nervous system reactivity under the stress of anticipating a predictable aversive stimulus.

Gogineni, A., King, S.M., Iacono, W.G., McGue, M., etal. (2006). Female Offspring of Alcoholic Individuals: Recent Finding on Alcoholism and Psychopathology Risk: Symposium Presented at the Research Society on Alcoholism, 2004, Vancouver Aruna Gogineni Chair. Alcoholism: Clinical and Experimental Research, 30, 377-387.
In the past decade, significant advances have been made in understanding how genetic and environmental factors contribute to alcoholism and other psychopathology
among children of alcoholic individuals. Potential biopsychosocial markers of risk (e.g., low level of response to alcohol, behavioral undercontrol, and family functioning variables) have been identi.ed and indicate that both individual and environmental variables are highly relevant. Despite these advances, studies have predominantly
focused on examining outcomes among sons of alcoholic individuals, with the consequence that relatively little is known about the risk for alcoholism and other psychopathology among daughters. Effective prevention and treatment strategies are predicated upon further knowledge of these risks among daughters as well as sons. This symposium will present recent .ndings using family, prospective, and cross-sectional research to elucidate the biopsychosocial correlates and the moderators of risk for alcoholism and other psychopathology among daughters from developmental trajectories spanning the periods of childhood, adolescence, and adulthood.
This symposium begins with a presentation by John Kramer in which high-risk daughters’ and sons’ alcohol and drug involvement are compared with respect to their predictors, drawn from demographic, familial, and personal domains. Next, Serena King focuses on the correlates of disinhibited behavior in males and females from adoptive and biological families, with an emphasis on parental alcoholism, genetic versus environmental in.uences, and differences between genders. This talk is followed by a presentation by Kristina Jackson, who examines the predictors of alcohol use disorders among young adults from high-risk and control families, including such factors as family history, negative affect, behavioral undercontrol, and childhood stressors. Finally, Aruna
Gogineni addresses the familial predictors of adult daughters’ alcohol problems and depression, focusing on the effects of maternal versus paternal alcoholism as well as family density of pathology.

Yoon, H.H., Iacono, W.G., Malone, S.M. & McGue, M. (2006) Using the Brian P300 Response to Identify Novel Phenotypes Reflecting Genetic Vulnerability for Adolescent Substance Misuse. Addictive Behaviors, 31, 1067-1087.
We used a novel approach to identify candidate alternative phenotypes for investigating genetic influence underlying substance use disorders (SUDs) in adolescents. The existing literature suggests that P300 amplitude reduction (P3-AR) observed in brain event-related potentials is associated with risk for SUDs generally, not just alcoholism. Using data from a community-based sample of 17-year-old male and female twins, we fit biometric models to P3 amplitude data to show that it is strongly heritable, especially in boys. The extant evidence coupled with our findings strongly supports treating P3-AR as an endophenotype indexing SUD risk. We then examined a set of 15 potential alternative phenotypes (e.g., frequent use of cannabis) to determine whether they were associated with P3-AR. The results indicated that almost all of these alternative phenotypes were associated with P3-AR, with larger effect sizes observed for boys. Given the strong association of these use phenotypes with P3-AR, which is itself an index of genetic risk for SUDs, we conclude that these use phenotypes may provide tools for finding vulnerability genes in adolescents who have yet to pass through the age of risk for SUDs.
© 2006 Elsevier Ltd. All rights reserved.

King, S.M., Burt, A., Malone, S.M., McGue, M. & Iacono, W.G. (2005). Etiological Contributions to Heavy Drinking from Late Adolescents to Young Adulthood. Journal of Abnormal Psychology, 114, 587-598.
The authors examined genetic and environmental contributions to stability and change in heavy drinking from late adolescence to young adulthood in a sample of 1,152 twin pairs. In men, heavy drinking was similarly heritable at ages 17 (h2 _ .57) and 20 (h2 _ .39), and its stability owed primarily to common genetic factors. In women, heavy drinking was less heritable than in men at ages 17 (h2 _ .18) and 20 (h2 _ .30) and its stability was primarily due to enduring shared environmental influences. P3 amplitude, an event-related brain potential marker of alcoholism risk, was less predictive of heavy drinking in women than in men, providing further support for the proposition that biological factors have less impact on heavy drinking in young adult women than in young adult men.

Legrand, L.N., Iacono, W.G. & McGue, M. (2005). Predicting Addiction. American Scientist, 93, 140-147.
In 1994, the 45-year-old daughter of Senator and former presidential nominee George McGovern froze to death outside a bar in Madison, Wisconsin. Terry McGovern’s death followed a night of heavy drinking and a lifetime of battling alcohol addiction. The Senator’s middle child had been talented and charismatic, but also rebellious. She started drinking at 13, became pregnant at 15 and experimented with marijuana and LSD in high school. She was sober during much of her 30s but eventually relapsed. By the time she died, Terry had been through many treatment programs and more than 60 detoxifications.
Her story is not unique. Even with strong family support, failure to over-come an addiction is common. Success rates vary by treatment type, severity of the condition and the criteria for success. But typically, fewer than a third of alcoholics are recovered a year or two after treatment. Thus, addiction may be thought of as a chronic, relapsing illness. Like other serious psychiatric conditions, it can cause a lifetime of re-current episodes and treatments.
Given these somber prospects, the best strategy for fighting addiction may be to prevent it in the first place. But warning young people about the dangers of addiction carries little force when many adults drink openly with-out apparent consequences. Would specific warnings for individuals with a strong genetic vulnerability to alcohol-ism be more effective? Senator McGovern became convinced that his daughter possessed such a vulnerability, as other family members also struggled with dependency. Perhaps Terry would have taken a different approach to alcohol, or avoided it altogether, if she had known that something about her biology made drinking particularly dangerous for her.
How can we identify people—at a young enough age to intervene—who have a high, inherent risk of becoming addicted? Does unusual susceptibility arise from differences at the biochemical level? And what social or environmental factors might tip the scales for kids at greatest risk? That is, what kind of parenting, or peer group, or neighbor-hood conditions might encourage—or inhibit—the expression of “addiction” genes? These questions are the focus of our research.

Carlson, S.R., Iacono, W.G. & McGue, M. (2004) P300 Amplitude in Non-Alcoholic Adolescent Twin Pairs Who Become Discordant for Alcoholism as Adults. Psychophysiology, 41, 841-844.
Past reports suggest that reduced P300 amplitude is associated with risk for alcoholism. We examined whether visual P300 amplitude could identify familial risk for alcohol disorders in individuals not known to be at risk at the time P300 was recorded. These individualswere twins from pairswhere neither twin had an alcohol disorder at age 17 but familial risk was established at age 20 when one twin developed an alcohol disorder whereas the other did not. Of special interest was the P300 of the unaffected twin recorded at age 17 when both twins were alcoholism free. We found reduced P300 in the unaffected twin compared to pairs where both members were continuously disorder free. Hence, P300 was reduced in alcohol disorder-free individuals whose twin siblings subsequently developed alcoholism, further supporting reduced P300 amplitude as an endophenotype indexing familial risk for alcoholism.

Elkins, I.J., McGue, M., Malone, S. & Iacono, W.G. (2004). The effect of parental alcohol and drug disorder on adolescent personality. American Journal of Psychiatry, 161, 670-676.
Objective: The relationship of parental alcohol or drug diagnosis to offspring personality was examined in a population based sample of 17-year-old twins (568 girls and 479 boys) participating in the Minnesota Twin Family Study. Whether offspring personality characteristics 1) are specific to the type of substance use disorder in parents (alcohol versus drug) and 2) are found in high-risk offspring without substance use disorders as well as in offspring with substance use disorders was investigated.
Method: Personality was assessed with the Multidimensional Personality Questionnaire; substance use disorders were assessed in person through diagnostic interviews.
Results: In both male and female offspring, parental history of alcohol dependence was associated with greater negative emotionality, aggression, stress reaction, and alienation but lower wellbeing; parental history of drug disorders was associated with lower constraint, control, harm avoidance, and traditionalism but higher social potency. Excluding offspring with a substance use disorder had virtually no effect on the statistical significance of these findings.
Conclusions: In contrast to findings in some adult samples, personality characteristics associated with a family history of substance use disorders are found even in adolescent offspring who have not yet developed these disorders themselves, suggesting that personality might be one indicator of familial risk for substance use disorders during this developmental stage. Personality profiles of offspring of parents with substance use disorders also show some diagnostic specificity, with constraint associated with parental drug abuse and negative emotionality with parental alcoholism.
(Am J Psychiatry 2004; 161:670–676)

King, S.M., Iacono, W.G. & McGue, M. (2004). Childhood Externalizing and Internalizing Psychopathology in Prediction of Early Substance Use. Addiction, 99, 1548-1559.
Aims: To examine the prospective relationships between childhood externalizing and internalizing disorders and substance use in early adolescence.
Design: Longitudinal, community-based study of twins (aged 11 at intake; aged 14 at follow-up).
Setting and participants: The sample was composed of twins participating in the Minnesota Twin Family Study, an epidemiological sample of twins and their families representative of the state population of Minnesota. A total of 699 twin girls and 665 twin boys participated at both time-points.
Measurements: Twins participated in in-person, life-time diagnostic assessments of the following childhood DSM III-R externalizing and internalizing disorders at age 11: conduct disorder, oppositional defiant disorder, attention deficit hyperactivity disorder, major depressive disorder and in addition, for girls only, overanxious disorder and separation anxiety disorder. At ages 11 and 14, substance use and abuse were assessed.
Findings: Externalizing psychopathology predicted having tried alcohol, nicotine and cannabis by age 14 as well as regular and advanced experience with these substances. Internalizing disorders showed weak effects, with only major depression at age 11 showing a significant relationship with substance use at age 14.
Conclusion: The results suggest that externalizing psychopathology is a robust prospective predictor of a variety of early onset substance use behaviors and is systematically related to degree of substance use involvement. The results also suggest that depression may predict initiation of licit substance use in early adolescence.

Krueger, R.F., Nichol, P.E., Hicks, B.M., Markon, K.E., Patrick, C.J., Iacono, W.G. & McGue, M. (2004). Using Latent Trait Modeling to Conceptualize an Alcohol Continuum. Psychological Assessment, 16, 107-119.
Recent research points toward the viability of conceptualizing alcohol problems as arrayed along a continuum. Nevertheless, modern statistical techniques designed to scale multiple problems along a continuum (latent trait modeling; LTM) have rarely been applied to alcohol problems. This study applies LTM methods to data on 110 problems reported during in-person interviews of 1,348 middle-aged men (mean age _ 43) from the general population. The results revealed a continuum of severity linking the 110 problems, ranging from heavy and abusive drinking, through tolerance and withdrawal, to serious complications of alcoholism. These results indicate that alcohol problems can be arrayed along a dimension of severity and emphasize the relevance of LTM to informing the conceptualization and assessment of alcohol problems.

Walden, B., McGue, M., Iacono, W. G., Burt, A. & Elkins I. (2004). Identifying Shared Environmental Contributions to Early Substance Use: The Respective Roles of Peers and Parents. Journal of Abnormal Psychology, 113, 440-450.
Although behavior genetic studies have suggested that early substance use is primarily environmentally mediated, no study has sought to identify the specific sources of environmental variance. Using data obtained from multiple informants, this study assessed the contributions of peer deviance and parent–child relationship problems to substance use in 14-year-old male and female twins (N _ 1,403) drawn from the Minnesota Twin Family Study (MTFS). All three phenotypes were influenced primarily by shared environmental variance (average c2 _ .51), as was the overlap among them. Moreover, peer deviance and parent– child relationship problems accounted for approximately 77% of the variance in early substance use. Findings also indicated that peer deviance, but not parent– child relationship problems, accounted uniquely for variance in early substance use.

Iacono, W.G., Malone, S & McGue, M. (2003). Substance Use Disorders, Externalizing Psychopathologies, and P300 Event Related Potential Amplitude. International Journal of Psychophysiology, 48, 147-178.
We hypothesize the existence of an inherited predisposition for a spectrum of behaviors and traits characterized by behavioral disinhibition. This externalizing spectrum includes childhood disruptive disorders, antisocial behavior, substance use disorders, personality traits related to behavioral under control, and the precocious expression of problem behavior. We further hypothesize that a genetically influenced central nervous system diathesis underlies this spectrum and is reflected in reduced P300 amplitude in a visual oddball event-related potential task. A review of evidence bearing on the model is derived from findings from the Minnesota Twin Family Study, a population-based, longitudinal investigation of twin youth. These findings indicate that the collection of attributes related to behavioral disinhibition is familial, heritable, and interrelated. Evidence supporting P3 amplitude reduction (P3-AR) as an index of genetic vulnerability for this externalizing spectrum includes its association with (a) familial risk for substance use and antisocial personality disorders, (b) diagnoses of childhood disruptive disorders and substance use disorders, (c) early onset of undersocialized behavior, and (d) quantitative phenotypes related to externalizing problems. In addition, the development of substance use disorders over a 3-year period is associated with P3-AR measured prior to their expression. These findings suggest that P3-AR indexes one aspect of the genetic diathesis for a spectrum of externalizing problem behavior.

Von Ranson, K.M., McGue, M., & Iacono, W.G. (2003). Disordered Eating and Substance Use in an Epidemiological Sample: II. Associations within families. Psychology of Addictive Behavior, 17, 193-202.
This study investigated familial associations of disordered eating (DE) with substance use and substance use disorders (SU/SUDs) in a community-based sample of 620 adolescent girls, their 310 mothers, and 299 fathers. Female participants completed structured interviews of lifetime anorexia nervosa, bulimia nervosa, binge eating disorder, and SU/SUD; daughters also completed a self-report measure of current DE attitudes and behaviors. Fathers completed interviews assessing lifetime SUD. Evaluation of independent and combined associations of mothers’ bulimic eating disturbance (ED) and parents’ SUDs with daughters’ DE/EDs and SU/SUDs revealed links between mothers’ ED and daughters’ DE but no relationship between EDs and SU/SUDs across generations. These results suggest that these problems are not cross-transmitted within families and suggest that the addiction model of eating disorders may be simplistic.

Carlson, S.R., Iacono, W.G., & McGue, M. (2002). P300 Amplitude in Adolescent Twins Discordant for Alcohol Use Disorders. Biological Psychology, 61, 203-227.
The sons of alcoholics have repeatedly been found to have reduced P300 amplitude. Further, quantitative behavioral genetic and molecular genetic studies indicating a genetic influence on P300 amplitude have fueled speculation that this component may be a biological vulnerability marker for alcoholism. To further explore this possibility, we examined P300 in adolescent twin pairs from an epidemiological sample who were (a) discordant for alcohol abuse/dependence, (b) concordant for alcohol abuse/dependence, or (c) concordant for the absence of alcohol abuse/dependence and other relevant disorders. For discordant pairs, the alcohol abusing/dependent twins’ amplitude did not differ from that of non-alcoholic cotwins. Pairs free of psychopathology had greater amplitudes than both alcoholism discordant and concordant pairs. P300 amplitude was more similar in monozygotic than dizygotic discordant pairs, suggesting a genetic influence on P300 amplitude in this group. The findings are consistent with P300 amplitude being a marker of vulnerability to alcohol use disorders.

Holdcraft, L.C., & Iacono, W.G. (2002). Cohort effects on Gender Differences in Alcohol Dependence. Addiction, 97, 1025-1036.
Aims: The present study investigated the presence of cohort effects on gender differences in the course, severity and symptomatology of DSM-III-R alcohol dependence in a community-based sample.
Design: A comparison of substance-related variables among men and women divided into two groups based on the median birth year of the sample was conducted.
Participants: Participants were 468 men and 132 women with life-time alcohol dependence, the vast majority of whom were born between 1941 and 1960.
Measurements: Substance use and DSM-III-R substance use disorders were assessed by a structured interview administered in person.
Findings: Individuals born after 1951 had higher rates of alcohol dependence. Among individuals with alcohol dependence, those born after 1951 had an earlier onset and longer duration of alcohol-related problems. Significant interactions indicated that these effects were stronger for women than men.
Conclusions: Risk for alcohol dependence appears to be rising in younger generations, and particularly for younger women, making them an important target group for prevention and treatment programs.

Malone, S.M., Iacono, W.G., McGue, M. (2002). Drinks of the father: Father’s maximum number of drinks consumed predicts externalizing disorders, substance use, and substance use disorders in preadolescent and adolescent offspring. Alcoholism: Clinical & Experimental Research, 26, 1823-1832.
Background: The maximum number of drinks consumed in 24 hr seems to be an interesting phenotype related to alcoholism. The goal of the present study was to determine in an epidemiologic sample whether this measure of drinking history in fathers predicted externalizing behavioral disorders, substance use, and substance abuse in preadolescent and adolescent offspring and whether any such associations would be independent of paternal alcohol dependence diagnoses.
Methods: Subjects were male and female twins from both age cohorts of the Minnesota Twin Family Study, a population-based longitudinal study, and were approximately 11 or 17 years of age, respectively, upon study enrollment. In both age cohorts, diagnoses of conduct disorder, oppositional defiant disorder, and attention-deficit/hyperactivity disorder served as outcome measures. In addition, measures of lifetime substance use and of the presence of symptoms of substance abuse were derived for the 11-year-old cohort when subjects were approximately 14 years old and diagnoses of substance abuse were derived for the older cohort at age 17. An extension of logistic regression using generalized estimating equations served to assess whether paternal maximum alcohol consumption predicted filial outcome measures.
Results: Paternal maximum alcohol consumption was consistently associated with conduct disorder, substance use, and substance abuse or dependence in male and female offspring. These associations were not mediated by a primary effect of paternal alcoholism.
Conclusions: Paternal maximum alcohol consumption was uniquely associated with those offspring characteristics most reliably found in adolescent children of alcoholic parents. This phenotype might supplement DSM diagnoses of alcohol dependence to reduce the number of false positives in genetic research.

Taylor, J.T., Malone, S., Iacono, W.G., & McGue, M. (2002). Development of substance dependence in two delinquency subgroups and non-delinquents from a male twin sample. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 386-93.
Objective: The effect of delinquency subtype on the development of substance dependence symptoms was examined. It was proposed that early-onset delinquents possess characteristics that increase their likelihood of developing substance dependence problems earlier and more rapidly than late-onset delinquents and nondelinquents.
Method: The development of alcohol, nicotine, and cannabis dependence symptoms (DSM-III-R) was examined over a 6-year period of adolescence (age 11–17) among 36 early-onset delinquent, 86 late-onset delinquent, and 25 nondelinquent boys from a large epidemiological twin sample. Multilevel/random coefficients models were used to compare groups on the rate of growth in number of symptoms over time.
Results: As expected, early-onset delinquents showed an earlier onset and a faster rate of increase in the number of cannabis and nicotine dependence symptoms than late-onset delinquents and controls. Both delinquent groups had a more rapid increase in alcohol dependence symptoms than controls.
The data showed that early-onset delinquency is associated with earlier onset of substance use disorder symptoms and more rapid acceleration of problems with drugs than late-onset delinquency. Treatments for boys with early-onset delinquency should account for their increased risk for drug use problems in adolescence and the potential effects of those problems on the course of antisocial behavior.
J. Am. Acad. Child Adolesc. Psychiatry, 2002, 41(4):000–000.

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