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.

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.

Holdcraft, L.C. & Iacono, W.G. (2004). Cross-generational Effects on Gender Differences in Psychoactive Drug Abuse and Dependence. Drug and Alcohol Dependence, 74, 147-158.
Background: Studies of patients with cocaine and heroin use disorders have shown gender differences in prevalence, course, and outcome.
These differences may be decreasing in successive generations. Less is known about gender differences in course and symptomatology for other illicit drug use disorders, especially in community samples.
Method: Participants (1323 men and 1384 women) who were biological or step-parents of twins and born in the 1940–1960s, from the Minnesota Twin-Family Study (MTFS) were divided into two cohorts based on the median birth year. A structured interview was used to assess DSM-III-R cannabis, amphetamine, cocaine and hallucinogen use disorders.
Results: There was a higher prevalence of each of these drug disorders and earlier onset of cannabis and amphetamine use disorders in later-born participants. For most drug use disorder categories, men and women were similar with respect to age of onset and severity of disorder but women had a shorter course of drug use disorders. Women with amphetamine disorders were atypical with respect to having a higher frequency of use but similar number of lifetime uses compared to men, and more emotional effects of amphetamine intoxication than men. In addition, women with amphetamine disorders were more likely to have anorexia nervosa than those without amphetamine disorders.
Conclusions: These results have several implications for prevention, etiology and treatment.
© 2003 Elsevier Ireland Ltd. All rights reserved.

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.

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.
©2003 Elsevier Science B.V. All rights reserved.

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.

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.
Conclusions:
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.