Christian Hopfer - US grants

DESCRIPTION (provided by applicant): This is a proposal to expand a family study of adjudicated adolescent boys and girls with Substance Use Disorders (SUD) and Conduct Disorder (CD). In this revised application, we propose to evaluate the families of 400 adolescent probands, identified through court records, as well as 200 controls and their family members. Expanding the study to include more families will allow for an adequate sample size to discriminate between different comorbidity models of SUD and CD and the assessment of parental and sibling influences on SUD and CD. DNA will be collected in order to assess for degree of genetic relatedness and non-paternity. The specific aims of the proposal are to: 1) test competing models of the comorbidity between SUD and CD in sibling pairs, where one of the siblings is an adjudicated adolescent, 2) examine the influence of parents and siblings on the development of SUD and CD in families with at least one adjudicated adolescent, and 3) compare the observed familial aggregation of SUD and CD between the proposed sample and a sample of families of youth in treatment for SUD and CD. SUD and CD are severe, life-threatening conditions of adolescence. Mortality rates among such adolescents reportedly are fivefold greater than among their age-mates. This research may lead to the identification of familial influences influencing the expression of these pathological behaviors. This may lead to improved phenotypes, improving the search for specific genetic or environmental causes of these destructive behaviors. The ultimate goal of this research is to reverse that process through therapeutic correction of those pathological genetic or environmental factors.

DESCRIPTION (provided by applicant): This is a proposal to expand a family study of adjudicated adolescent boys and girls with Substance Use Disorders (SUD) and Conduct Disorder (CD). In this revised application, we propose to evaluate the families of 400 adolescent probands, identified through court records, as well as 200 controls and their family members. Expanding the study to include more families will allow for an adequate sample size to discriminate between different comorbidity models of SUD and CD and the assessment of parental and sibling influences on SUD and CD. DNA will be collected in order to assess for degree of genetic relatedness and non-paternity. The specific aims of the proposal are to: 1) test competing models of the comorbidity between SUD and CD in sibling pairs, where one of the siblings is an adjudicated adolescent, 2) examine the influence of parents and siblings on the development of SUD and CD in families with at least one adjudicated adolescent, and 3) compare the observed familial aggregation of SUD and CD between the proposed sample and a sample of families of youth in treatment for SUD and CD. SUD and CD are severe, life-threatening conditions of adolescence. Mortality rates among such adolescents reportedly are fivefold greater than among their age-mates. This research may lead to the identification of familial influences influencing the expression of these pathological behaviors. This may lead to improved phenotypes, improving the search for specific genetic or environmental causes of these destructive behaviors. The ultimate goal of this research is to reverse that process through therapeutic correction of those pathological genetic or environmental factors.

DESCRIPTION (provided by applicant): This application continues a multisite collaboration, initiated under DA 012845, to address critical issues in the genetic epidemiology of adolescent onset antisocial drug dependence. Addressing these issues requires sample sizes greater than a single site can reasonably attain, as well as the multidisciplinary expertise of psychiatrists, psychologists, and behavioral and molecular geneticists, that is difficult to provide at a single site. This collaboration includes longitudinal assessment of previously studied probands and siblings, and adds community controls. It will yield a total of ~800 clinical probands, together with their siblings, to assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading. After allowing for desistance, we anticipate a final sample of ~600 persistent cases, together with their siblings, and a matched sample of ~600 control subjects, for genetic association analyses of persistent, adolescent onset, antisocial substance dependence. The current application will use dense SNP association mapping to identify genetic loci predisposing to this pattern of behavior. The specific aims of the project are as follows: 1) We will complete the five year follow-up assessment of ~800 clinical probands, aged 19 though 23 years at follow-up, and their siblings, and ascertain a sample of matched control subjects from our existing databases together with 300 newly ascertained control subjects. The new assessments will be conducted at the San Diego and Denver sites. 2) We will assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading on these. The data set we are collecting would, even in the absence of a single DMA sample, represent a unique, and unsurpassed, research resource for studying the development and familial influences on adolescent antisocial drug dependence. 3) We will use Affymetrix SNP chip technology to genotype an average of 25 SNPs in each of 200 candidate genes for drug dependence vulnerability and/or conduct disorder. 4) We will conduct association analyses using the -600 persistent cases and their ~600 matched controls, and then conduct confirmatory tests of the best signals using a within-family association analysis (Laird and Lange, 2006). These analyses will confirm the significance and robustness of genetic associations with adolescent onset persistent antisocial drug dependence. 5) Through a continuation of our NIDA Genetics Consortium data sharing agreement, we will share all the core substance dependence and psychopathology phenotypic data, and DNA from lymphoblastoid cell lines established for the multisite samples. Our Affymetrix SNP chip will be made available, at cost, to any qualified researcher.

DESCRIPTION (provided by applicant): The number of US citizens with substance use disorders or where substance use contributes to other health disorders is expected to continue to be high over the next several decades. Programs are needed to provide trainees with the skills to conduct research that helps prevent and treat substance use disorders. Physician scientists bring a unique perspective to substance use research and are a critical component of future advances in this area. This program will focus on recruiting and training medical students, preparing them for careers as substance use researchers. The program includes both core and individualized curricular components. Core curricular components include a seminar on substance use and disease, an ongoing work-in-progress seminar with both faculty and trainee involvement, and a seminar related to the Responsible Conduct of Research. The individualized curricular components include both class work and direct project experience, including dissemination, mentored by an experienced substance use researcher. Both short-term intensive and longitudinal training components are included; students will enter the program as first-year medical students and be involved in the program over all 4 years of medical school. Two new students per year will be recruited for a total of four students in the program at any one time. There will be ongoing evaluation of the program including both student feedback and outcome assessment. This will include short (e.g student satisfaction), intermediate (early publication and attitude changes), and long-term (long-term publication rates and success at receiving research grants) outcomes. A Senior Advisory Board will provide oversight for the program and ensure use of the outcome data for ongoing quality improvement of the program.

DESCRIPTION (provided by applicant): This application for a mid-career investigator award seeks funds to support the PI's research career and mentoring activities. Funds from the award will allow the PI to expand his mentoring activities, develop additional skill sets in longitudinal data analysis and expand his program of research that involves understanding the etiology and longitudinal course of adolescent-onset substance use disorders. This award will result in relief from substantial administrative and clinical responsibilities as the Psychiatric Director of the Addiction, Research and Treatment Services (ARTS), a large treatment program affiliated with the University of Colorado Denver Anschutz Medical Campus. Effort will be redirected toward mentoring activities, career development, and research activities. The PI is currently involved in a number of studies that are examining adolescent and young adult substance use disorders, both from a clinical, behavior genetics, and molecular genetic perspective. The PI will expand his research program by expanding his current research projects to gather more information about adolescent perceptions and patterns of marijuana use in the light of the recent medical marijuana explosion as well as conduct a longitudinal study that will follow a sample of both clinical and community adolescents every 6 months for 3 years to examine the development of marijuana use patterns and associated HIV-risk behaviors.

DESCRIPTION (provided by applicant): The research proposed in this application aims to understand genetic and environmental factors that promote desistance or continuation of problematic substance use and associated high-risk behaviors that began in adolescence. We propose an ~12-year follow-up (6 years after an initial 6-year follow-up) of an extremely affected adolescent sample as they transition into adulthood; this is a critical developmental period when we expect a portion of these individuals to decrease or desist problematic substance use and associated high-risk behaviors, while others will persist with the most serious, destructive behaviors leading to devastatingly high rates of morbidity and mortality. Our central goal is to understand the genetic and environmental factors that delineate these life trajectories. Results from our longitudinal research demonstrate that adolescent-onset substance users, who primarily exhibited abuse of and dependence on marijuana, nicotine, and alcohol during adolescence, progressed in the severity of their substance use five years later. As young adults, they report dramatically high rates of lifetime cocaine (29.2%), amphetamine (29.2%), and opiate (10.8%) use disorders as well as HIV/AIDS-related risk behaviors such as injection drug use (11%) and risky sexual behaviors. Indeed, when compared with community samples, these individuals report more than twice the number of lifetime sexual partners and a 33% higher rate of unprotected sex. Furthermore, they exhibit alarming rates of adult incarceration (55%) and early death (2.6%). This proposal extends our multiple-PI collaboration focused on the genetic epidemiology of adolescent-onset drug dependence. The three specific aims are to: 1) Identify distinct developmental trajectories of substance use, antisocial, and HIV risk behaviors in probands and siblings from adolescence to adulthood. a) Test initial characteristics of the adolescents, such as sex, severity of early onset substance use disorders (SUDs) and conduct disorder (CD), and neurocognitive functioning (e.g., disinhibition) that predict these trajectories and b) Test whether adult resources such as treatment for SUDs, housing stability, occupational stability, and social support are associated with these trajectories. 2) Determine the genetic and environmental architecture of developmental trajectories of substance use disorders, antisocial and HIV risk behaviors. a) Test the moderating role of social context, such as SES, criminal justice involvement, substance abuse treatment/self-help involvement, and stressful life events, in altering genetic influence and b) Test whether moderating effects vary across developmental periods (adolescence, young adulthood, and adulthood). 3) Test the influence of shared versus specific etiologic influences on measures of SUDs, antisocial behaviors, and HIV risk behaviors across development.

This supplemental grant proposes to add questions to extend the aims of the parent project by collecting additional data related to COVID-19 including financial hardships, social/interpersonal problems, stress, mental health, and substance use changes. Data will also be collected on whether participants are essential workers, were exposed to COVID-19, or have been diagnosed with COVID-19. Parent grant Aim 1: Effect of RML on substance use/misuse, mental health, & psychosocial function Aim 1 extended: Effect of COVID-19 pandemic and RML on substance use/misuse, mental health & psychosocial function. We will test the hypothesis that access to RML increases the likelihood that the stress and disruption associated with COVID-19 will lead to increased marijuana use and abuse. Relatedly, we will test the extent to which increased marijuana use, related to RML and stress/disruptions from COVID-19, is accompanied by increases in other substance use, mental health disorders, or psychosocial dysfunction. Parent grant Aim 2: Individual differences in the effect of RML Aim 2 extended: Examine individual differences in the effect of COVID-19 pandemic and RML. Examine individual differences in the effects of COVID-19 and legalization by leveraging parallel multi-wave longitudinal twin studies in CO and MN, which both began collecting substance use, psychopathology, and psychosocial function during the twins' adolescence. This supplemental assessment will allow us to: a) identify how COVID-19 differentially impacts individuals depending on legalization and prior exposure to marijuana; b) examine how individuals differ in their vulnerability and resilience to the effects COVID-19, in the context of legalization, based on their individual level of risk (e.g., prior diagnosis of anxiety or depression); and c) examine if there are differential associations between COVID-19 and substance use/dependence, mental health, and psychosocial problems depending on legalization status and gender.

The primary goals of this K24 competing renewal application are to enable Christian Hopfer, M.D. to conduct career development activities to enhance his patient-oriented addiction research and to provide high-quality mentorship to early-career investigators. The renewal will enable Dr. Hopfer to have protected time to devote to career development and mentoring of clinical researchers. Dr. Hopfer was promoted to Full Professor of Psychiatry at the University of Colorado School of Medicine due to the success of his research, teaching, and clinical program. Dr. Hopfer's major goals of his initial award were accomplished with obtaining and leading a NIDA funded R25 medical student research education program, acting as the executive director of the Developmental Psychobiology Research Group (DPRG) whose affiliated T32 program was renewed, obtaining new research funding, and mentoring junior investigators. Dr.Hopfers' research plan for this renewal application involves continued work as a PI on NIDA funded research focused on understanding genetic and environmental influences on the progression or desistance of substance use disorders among high-risk youth utilizing a joint twin/family study design as well as understanding the impact of legal marijuana access on psychiatric and behavioral outcomes. He plans to expand his search for biomarkers for substance use disorders that have been previously conducted utilizing molecular genetic approaches to now include proteomic, metabolomics, RNA-seq, and lipidomic approaches. Dr.Hopfer mentors trainees in multiple areas of research training including: 1) Understanding clinical aspects of substance use and abuse, 2) Twin/family and molecular approaches to examining the etiology of substance use and correlated disorders, 3) Preparing scientific papers and presenting findings, 4) Developing and writing successful project proposals, and 5) conducting responsible research. He will accomplish his training mission through individual and group mentoring and collaborating with key colleagues with expertise in biostatistics and state of the art measurement technologies for identifying biomarkers of substance use.