William G. Iacono - US grants

A unique group of 175 patients experiencing their first lifetime episode of psychosis has been gather. And an attempt was made to recruit every case of first-episode psychosis that appeared in metropolitan Vancouver, Canada, over a two and one half year time span. The project focus was on psychosocial and biological factors associated with schizophrenia and the course of illness. Follow-up data are available at 9 months, 18 months, and then 5 years after initial illness. The data include measures that tap an array of psychosocial characteristics, putative psychophysiological markers of genetic vulnerability to schizophrenia, brain morphology, family history, premorbid personality, treatment history, and detailed clinical diagnostic data. Comparative data are available on a group of normal control subjects (n =141) recruited from the same community. To evaluate the potential of the psychophysiological measures as markers of schizophrenia, all available first-degree relatives of the first-episode psychotic patients and the normal subjects were also recruited. There is no data set comparable to this anywhere else and it is unlikely to replicated. While a number of publications have emerged based on this study, the rich data provide exciting opportunities to explore the interaction between biological and psychosocial factors in predicting the course of a baffling, disabling, and socially wasteful illness.

The Minnesota Twin Family Study (MTFS) seeks to identify genetic and environmental influences on the development of substance abuse (SA) and associated psychological disorders. An epidemiologically based sample of approximately 670 male pre-adolescent and adolescent twin pairs and their parents (a total of 2680 individuals) are undergoing a one-day comprehensive assessment that includes (1) mental health, (2) substance use and abuse history, (3) psychophysiological markers of risk, (4) personality/interests/social adjustment, and (5) environmental moderators of risk. Two cohorts are being assessed: twins are first assessed either when they are 11 years old, just prior to their initial experimentation with alcohol and other drugs, or at age 17, prior to the establishment of adult drinking and drug use patterns and the onset of adult psychological disorders. The sample is selected in such a way that approximately 40% of the twins have one or both biological parents with a DSM-III-R diagnosis of Substance Dependence (i.e., High Risk), 20% of twins have one or both biological parents with a DSM-II-R diagnosis of Substance Abuse but not Dependence (i.e., Medium Risk), 10% have one or both biological parents with a psychiatric disorder but not a SA diagnosis (i.e., Psychiatric Controls), and 30% of twins have both biological parents with no psychiatric or SA diagnosis (i.e., Controls). The project is designed as a prospective study of the etiology of psychoactive SA and related disorders. We are requesting funding to complete the last year of intake recruitment, to continue our yearly telephone/mail follow-up assessment, and to reassess the sample in our laboratory at 3-year intervals as the twins progress through the major life changes that characterize adolescence and early adulthood. The focus of analysis of the cross-sectional data will be on the high-risk aspects of the design as well as on understanding adolescent drug use and abuse from a behavioral genetic perspective. That is, we will seek to (1) identify early markers of risk, (2) characterize the genetic and environmental determinants of individual differences in these markers, and (3) identify interactions between biological risk status and environmental factors. Our longitudinal analyses will focus on how genetic and environmental factors mediate the development of substance use and abuse behavior, with special emphasis on how changes in the gene- environment interaction influence the developmental course of SA and related disorders. Additionally, our study of male adolescent twins parallels a proposed study of 600 female adolescent twins and their parents. This will provide us with the unique opportunity to identify sex differences in the origins of substance use and related disorders and determine whether and how those sex differences interact with genetic and environmental markers of risk.

DESCRIPTION (provided by applicant): We seek to continue the longitudinal study and data analysis of two population-based cohorts consisting of 666 twin pairs. The younger cohort, originally recruited at age 11, prior to significant substance use, will be followed through age 24-25. The older cohort, originally recruited at age 17, will be assessed through age 29-30. We hypothesize that an inherited predisposition to substance use disorder (SUD) is expressed through psychiatric, personality, psychosocial, and psychophysiological characteristics related to behavioral disinhibition and negative affective states that can be traced to pre-adolescence. Our findings to date suggest that externalizing disorders are highly comorbid and familial, associated with the personality dimension of constraint, and predictive of the development of adult antisocial behavior and SUDs. The liability for this collection of attributes is heritable and associated with reduced amplitude of the P3 event-related potential and individual differences in autonomic reactivity. However, findings from our younger cohort indicate that during early adolescence, a substantial shared environmental contribution to the development of externalizing and SUDs is present, with specific environmental factors like parent-child conflict likely to have etiologic significance. The personality dimension of negative emotionality and internalizing psychopathology are also associated with the development of SUDs, but predicted effects are less consistent than for behavioral disinhibition. We aim to identify mechanisms through which genetic and environmentally mediated risk factors translate into outcomes and understand how important life transitions contribute to the persistence and desistance of substance abuse. We will also establish immortalized DNA cell lines to facilitate future studies examining candidate gene associations with SUD phenotypes, investigate trajectories related to the development of SUDs using latent growth modeling, and evaluate models for gene-environment contributions to their development.

DESCRIPTION (Applicant's Abstract): Although externalizing psychopathology such as attention-deficit hyperactivity disorder (ADHD) and conduct disorder (CD) have been consistently associated with the development of substance abuse, and although genes appear to influence risk for substance use disorders and these related forms of psychopathology, relatively little is known about the mechanism of genetic influence or the processes by which genetic factors combine with non-genetic factors to affect the development and course of substance abuse and these related behavioral disorders. In order to address these issues, we propose to initiate a longitudinal study of 400 pairs of 11-year-old twins, their mothers and their fathers. Twins will be identified from birth records and selected so that 314 of the pairs will have at least one member with ADHD, early-onset CD, or both. An additional, 86 pairs without ADHD or CD will also be included. When these 314 affected pairs are combined with adolescent twin pairs from our other ongoing research projects, we will have more than 500 pairs of twins having at least one member with either ADHD or early-onset CD (yielding over 700 individuals with one of these diagnoses), and over 650 twin pairs where both members have neither disorder. Twins and the parents will be initially assessed in-person at age 11, followed subsequently with brief telephone interviews annually and with a follow-up in-person assessment every three years. The in-person assessment will include comprehensive measurement of: 1) psychiatric status, 2) psychophysiological markers of risk, 3) individual-level risk factors including personality and achievement, and 4) environmental risk factors including attachment to parents, attachment to schools, and peer group models. For the initial period of funding, analysis of the age 11 intake and age 14 follow-up data will focus on characterizing genetic and environmental contributions to early onset substance use. Towards this end we will: 1) investigate the relationship of ADHD and early-onset CD with known risk factors for adolescent substance use (e.g., family and peer relationships) and with adolescent substance use onset prior to age 15, 2) complete biometrical analysis of the risk factor and diagnostic data to estimate the degree to which genetic and environmental factors contribute to individual differences on these factors, and 3) investigate genotype-environment interactional and correlational models of the contribution of ADHD and disinhibitory psychopathology on early onset adolescent substance use. Our intent is to continue to follow this cohort through early adulthood so that the applicability of these models for adult substance abuse can be assessed.

[unreadable] DESCRIPTION (provided by applicant): Genetically influenced childhood disruptive disorders, such as attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) have been consistently associated with the later development of substance-use disorders (SUDs). Yet relatively little is known about the mechanisms of genetic influence, or how genetic factors combine with specific environmental risks in the creation of these disorders, their maintenance, and their progression on to SUDs. Five years of renewal funding is sought so that we may work to explicate these developmental processes. We have collected a large, community-based pre-adolescent sample, with equal representation of males and females that has been enriched for the presence of ADHD, CD, and ODD. Composed of twins and their parents, our sample is genetically informative, providing for biometric modeling of the twin data as well as modeling of parent-offspring transmission effects and we obtain DNA samples on all participants. We also assess a wide array of possible experiential risks, including parent-child relationships, parental monitoring, social support networks, neighborhood conditions, school-related experiences, and peer-group characteristics using self-report and in person interview methods involving multiple informants (parents, children, teachers). Thus, in combination, we have the potential to address important hypotheses regarding the relationship between ADHD, CD, ODD and SUDs, including those that incorporate theories of gene-environment correlation and gene-environment interaction. Our initial funding allowed 500 pairs of 11-year-old twins and their parents to complete a day-long, inperson assessment. Their first follow-up assessment, at age 14, has begun. The additional requested five years of funding will allow for the completion of the age-14 assessment as well as the re-assessment of most of these individuals at age 17. The combination of this enriched sample with cases from our other ongoing research projects will yield more than 250 individuals with ADHD and 600 with CD by age 14. This high-risk sample will have comprehensive, longitudinal data and is well suited to investigate gender effects. During the next five years, we aim to understand gene-environment interplay that culminates in substance misuse and early-onset SUDs. Towards this goal we will work to: 1) characterize the inherited vulnerability for SUDs, including the role psychophysiological indicators and candidate genes play; 2) learn how early adolescent problem behaviors influence the course of SUD development; 3) delineate the role of intra and extra-familial socializing agents; 4) clarify the role of negative emotionality; and 5) address questions regarding the role of gender, including whether the inherited vulnerability varies by gender, and whether gender moderates the association between liability markers, environmental risk, and later substance-use problems. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): We propose using established longitudinal studies of 7300 parents and twin children to investigate how gene environment interplay influences the development of substance abuse (SA). Our focus is on children assessed repeatedly, beginning in pre-adolescence at age 11 and then again at approximately ages 14, 17, 20, 24, and 29, making it possible to examine the development of individual differences within narrowly defined age ranges that correspond roughly to key life transitions associated with important changes in environmental context (starting high school, leaving the parental home, exposure to new peers, etc). Our studies involve representative, community based samples with high participation rates, and thorough age appropriate, psychometrically sound assessments covering 1) substance use, misuse, and dependence; 2) disorders, personality traits, and behaviors related to behavioral disinhibition; 3) psychophysiogical endophenotypes for SA risk; and 4) environmental adversity derived from multiple domains (family relationships, trauma, peer group quality, exposure to substances, etc.) over multiple developmental stages. We propose obtaining blood-based DMA from approximately 5000 study participants which, along with deidentified personal data, will be added to the NIDA Genetics Consortium (NGC) public repository. We will obtain consent to participate in this GEDI initiative from an additional 2300 individuals whose data will already be part of the NGC. We will carry out a 2-stage genome wide association study using a 1M SNP bead array with 1000 parents followed by confirmation genotyping with an additional 2700 parents using three SA related latent phenotypes focused on a) SA risk, b) behavioral disinhibition attributes, and c) brain electrophysiology (event related potentials and oscillations). These three quantitative phenotypes will be developed and refined early in the funding period so as to capture complementary aspects of genetic risk for SA similarly in parents and young adult offspring. Offspring (N=3582) will then be genotyped using candidate genes identified in the parent study as well as in the evolving SA literature. A composite measure of environmental adversity will also be developed and used in hypothesis driven tests of GxE effects in offspring that include examination of the developmental specificity of effects and their replicability across related measures, developmental time points, and offspring samples. Also included will be hypothesis-generating exploratory analyses that take advantage of the richness of the phenotypic data available from our families and the rapid pace of development in molecular biology and statistical genetics. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Adolescence and emerging adulthood represent an important developmental period during which substance use, misuse, and abuse occur concomitantly with important changes in neurocognitive development, mental health, and the social environment, with consequences for adult adjustment. Existing literature linking the effects of youth substance use to adult adjustment demonstrates the importance of these factors, but is largely correlational and cross-sectional, and leaves equivocal their causal role. Poor adult adjustment may be the result of youth substance misuse, including possible neurotoxic effects on brain development during this sensitive period. However, factors present prior to substance use initiation, such as genetic liability, pre- existing brain anomalies reflectng the manifestation of genetic risk, contextual risk, and comorbid disorders such as childhood disruptive disorders (CDDs), influence both adolescent substance exposure and adult outcomes. Existing research has typically not accounted for such factors. Thus, even the few longitudinal studies that exist are limited in the inferences they permit. We propose extending a prospective study of 453 twin pairs, first assessed at age 11, to determine young adult outcomes at age 24. To increase the likelihood that misuse of substances would be widespread and to ensure sufficient representation of high-risk females, half of our community-based twin sample was enriched for the presence of CDDs; the other half was selected at random and is thus representative of twins born in Minnesota. Study participants completed a day-long in- person intake assessment that included substance use, mental health, overall adjustment, environmental risk and protective factors, electrophysiological measurement, academic achievement, and cognitive ability. Participants were re-assessed at age 14, when many were initiating substance use, and again at age 17, when substance misuse was becoming apparent. Our sample's current value derives from the wealth of data already gathered on the timing, duration, frequency, and intensity of exposure to specific substances coupled with our careful assessments of the twins' behavioral, environmental, and familial characteristics throughout adolescence. We will capitalize on the value of this sample by undertaking a comprehensive assessment of age-24 outcomes that broadly covers substance use disorders, mental health (including persistence of CDDs), and psychosocial, electrophysiological, and neuropsychological outcomes. A subsample of 216 twin pairs will also undergo an MRI assessment, adding to the uniqueness of our study. Our data analytic strategy emphasizes the innovative application of a co-twin differences design, a powerful method for clarifying effects due to substance use from those due to unmeasured confounding factors, including genetic factors. This novel approach capitalizes on the differences in the history of substance misuse that occur naturally within twin pairs as they grow up, allowing us to separate the effects of substance abuse from familial and psychosocial risk factors that predate substance exposure on their overall adjustment and brain functioning as adults. 1

? DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the Twin Hub of the ABCD-USA Consortium is in response to RFA-DA-15-015; the proposal includes the University of Minnesota (hub leader), Virginia Commonwealth University, Washington University, and the University of Colorado to prospectively determine neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 800 twin pairs, ages 9-10 years, from four sites whose researchers are leaders in twin research, SU and abuse, and neuroimaging of cognitive and emotional functioning will be tested, together with 700 singletons, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD-USA Consortium. Participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) effects of substance use patterns on the adolescent brain; 2) effects of substance use on behavioral and health outcomes; 3) bidirectional relationships between psychopathology and substance use patterns; 4) effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) gateway interactions between use of different substances. The Twin Hub proposes to use classic and co-twin control designs to study genetic vs. environmental contributions to adolescent brain/behavioral development and how these contributions predict SU propensity. Using sophisticated growth trajectory modeling techniques, we will also identify the genetic and environmentally- determined consequences of substance use on brain and behavioral development, including the assessment of gene-by-environment interactions. In addition, we will develop biospecimen resources for future studies of genomic, epigenomic, metabolomics and microbiome changes that may influence substance use and its broad health consequences. Specific to this Twin-Hub, we will obtain baseline and follow-up serum, saliva, and in some cases gut microbiota from biological samples. This work enriches the full ABCD-USA Consortium given that disentangling G and E contributions to individual risk for addiction and sensitivity to SU's neurocognitive effects has highly significant public policy and prevention-based implications.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child's changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.