The vision of this Research Education Program is to train the next generation of researchers who can create and apply state-of-the-art statistical genetic methods in order to evaluate data on substance use, abuse and dependence (SUAD). The VIPBG Statistical Genetics Research Education Program (SGREP) provides research education opportunities and infrastructure support to promising and innovative junior researchers who wish to develop a focus on statistical genetic methods with special emphasis on substance abuse research. Specifically, the program is designed to bring together researchers from multiple academic backgrounds to create opportunities to investigate research questions in a multidisciplinary setting. VIPBG itself comprises faculty with appointments in the Departments of Psychiatry or of Human and Molecular Genetics, or both. The faculty for SGREP are drawn from VIPBG, the Departments of Biostatistics, Pharmacy and Pharmacology/Toxicology. As opposed to other training grant mechanisms (such as the NRSA, T32 or K32 mechanisms), the R25 provides infrastructure support for the integration of multidisciplinary and diverse expertise, an approach to which the VIPBG is strongly committed. This integration is vital if we are to address the complex problems of the genetic epidemiology of substance abuse.
Purpose and Objectives
The overall goal of this research education program is to provide an environment that encourages the development of statistical genetics methodology which is suitable for the analysis of data on substance use abuse and dependence at the highest levels. Two research focus areas are addressed, advanced genetic epidemiology (AGE) and statistical molecular genetics (SMG). Accordingly, we have structured a research education program that will enhance interdisciplinary research, something we believe to be essential to conducting research in this field, and which is a critical component of NIDA’s mission. The research education program consists of two components. First is pre-doctoral research education, which recruits potential future investigators to the area at the earliest time in their careers. This component will accelerate the development of focused substance abuse statistical genetics research by creating a cadre of students who are focused on this research area at the outset of their research education. Second is the post-doctoral component, which recognizes that many promising young researchers have obtained their early training in areas related to, but not focused on, the genetics of substance abuse. This flexible 2-3 year postdoctoral research education component is intended to guide young investigators to this field of study and to provide them with integrated and focused research experience in the statistical genetics of SUAD. Research education is targeted to individuals trained in biostatistics, human genetics and medicine. The goal of the program is to foster the career development of independent investigators who will contribute to the efforts of the VIPBG and other institutions nationally. To accomplish this goal we will: 1) offer a multidisciplinary integrated research education program with a range of research opportunities; 2) fund two pre-doctoral and three postdoctoral participants in emerging research areas of the statistical genetics of substance use and abuse; 3) provide research experience and intensive mentoring to researchers from diverse academic and ethnic backgrounds; 4) create a specialized curriculum that integrates strengths in statistical genetics and substance abuse research at VCU; and 5) disseminate these materials via the internet in the form of websites, webcasts and podcasts, and through week-long intensive workshops.
The Advanced Genetic Epidemiology Program (AGE) – Faculty with strong emphasis on AGE are Michael Neale, PhD, Kenneth Kendler, MD, Lindon Eaves, DSc, Hermine Maes, PhD, Robert Balster, PhD). The main research focus of the AGE program is the development of novel statistical methods and their implementation in software for the analysis of SUAD and its associated complex traits. The primary research areas within this program are: the measurement and classification of substance use and symptoms of abuse and dependence; interactions and correlations among genetic, environmental and developmental factors, exposure to deviant peer groups, substance availability, and exposure to substance use in the home environment, handling of missing data and under-reporting; joint analysis of genetic and environmental risk factors for substance initiation with those for development of abuse and dependence conditional on initiation; modeling polyabuse and its risk factors; comorbidity with psychiatric disorders; trajectories of the development of patterns of use; the analysis and interpretation of repeated-measure data on substance use disorders; modeling cross-informant reporting; statistically rigorous integrated etiologic models for substance use disorders including both genetic and environmental risk factors; models for development and the interaction over time of genetic susceptibility with environmental risk exposure; and the interpretation of bivariate and multivariate data from relatives to assess the relationship of genetic and environmental risk factors for abuse and dependence across different classes of psychoactive substances. New statistical methods developed in this program usually require testing via simulation studies, which in turn often demands substantial computational resources. VIPBG maintains its own computational cluster and has access to others for this purpose, so participants will be able to conduct simulations and analyses in a timely fashion. Development of software requires understanding of the capabilities and limitations of available programs and programming skills at multiple levels that can be used to overcome these shortcomings. It also requires cost-benefit analysis to evaluate how problem-specific and computationally efficient vs. how general and user-friendly the resultant product is to be. Training in innovative modeling, software development, applied analysis and dissemination are the key components of this program.
Statistical Molecular Genetics Program (SMG) – Faculty with strong emphasis in this area of focus are: Edwin van den Oord, PhD, Sam Chen, PhD, Michael Neale, PhD, Lindon Eaves, DSc, Mike Miles PhD). The SMG program initially seeks to identify polymorphisms on the human genome that confer risk for the initiation and persistence of substance use. An immediate secondary goal is to identify the mode of action of these variants through bioinformatics, proteomics, metabolomics and statistical modeling of biochemical pathways. This effort is being conducted by multiple investigators and in both human and model organisms. Design and statistical analysis issues are considerable, often involving extremely large datasets. Research areas within this program include: linkage, candidate gene and whole genome association studies; large scale experimental and statistical analyses of SNPs and haplotypes; population stratification and admixture; epistatic interactions; gene expression in model organisms; microarray experiments; data-mining and false discovery. Especially synergistic with the AGE focus are the use of gene association findings to investigate GxE interaction, comorbidity, pathology and development, and causal mechanisms. Further interrelation exists with three themes that pertain to the interplay of genotypes and environment: vulnerability, resilience, and protective factors; correlations between environmental factors and health problems; and sensitivity to environmental fluctuations. For these themes we will further develop and specify models that give greater insight into the nature of the genetic effects on SUAD and its related risk factors. and demonstrate these models using four existing samples in which genotype-phenotype associations have been found. Finally, methods to personalize medicine that exploit findings from these areas bring a translational component.