There are important contributions to risk for drug addiction by both genetic and environmental factors. Genome-wide association studies (GWAS) of complex diseases, including drug addiction, have begun to yield successes. Under this existing data program announcement, we propose a Post-GWAS analysis of initiation, dependence and cessation of alcohol, tobacco and illicit drugs in a population- based sample composed of 3 largely African-American cohorts ascertained in Baltimore, Maryland and followed intensively from childhood through young adulthood. We use the term 'Post-GWAS' to describe an analytic plan that derives objective hypotheses from innovative meta-analyses of publicly available GWAS data. This Post-GWAS study of drug use trajectories takes advantage of genetic, environmental, and developmental phenotypic data in 3 cohorts ascertained by the Johns Hopkins Prevention Intervention Research Center (PIRC). The goal of the PIRC research, commencing in 1985, is to examine the role of individual, social and neighborhood-level factors on developmental transitions in drug use in a largely African Americans sample followed from 1st grade into adulthood. The proposed work is innovative in that our Post-GWAS approach will use information extracted from existing, publicly-available GWAS of drug abuse-related traits to generate genetic hypotheses. This formal synthesis will be accomplished via meta-analysis, leading to a small set (N~500) of risk SNPs, genes, and profile scores for inclusion in subsequent analyses in the PIRC Cohorts. A second unusual aspect is the plan for a systematic scan of the influence of individual and environmental factors on three important aspects of the developmental trajectory of drug use and dependence-- initiation, dependence, and cessation-on three distinct substances: alcohol, tobacco and illicit drugs. The intensive follow-ups of the first graders over decades include a wide range of environmental factors, measured on a host of objective and self-reported indicators. A third innovative aspect is the plan to carry these two risk domains-- Post-GWAS genetic risk factors and PIRC-specific individual and environmental risk factors-- into longitudinal modeling of drug use trajectories. Our approach will investigate both drug-specific and common (general liability) effects as well as the moderating or mediating effects of the environment. The research is significant because the results will identify etiologic pathways in African Americans that will elucidate our understanding of drug use disorders and lead to enhanced efforts at treatment and prevention. Findings from this innovative and cost-effective project could have a significant impact on the creation of developmentally-appropriate, community-wide prevention programs targeted at urban-dwelling African Americans.

Public Health Relevance

Substance use disorders are a significant public health problem. We propose to harvest publicly available genome-wide data and existing objective measures of the environment to inform a focused set of hypotheses on gene-environment influences on tobacco, alcohol and marijuana initiation and use trajectory from adolescence into adulthood. The work will be done in several existing, already-genotyped, large (Total Genotyped N>1600), NIDA-funded, largely African American Cohorts ascertained in Baltimore, MD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA036525-02
Application #
9093763
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Weinberg, Naimah Z
Project Start
2015-07-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Musci, Rashelle J; Fairman, Brian; Masyn, Katherine E et al. (2018) Polygenic Score × Intervention Moderation: an Application of Discrete-Time Survival Analysis to Model the Timing of First Marijuana Use Among Urban Youth. Prev Sci 19:6-14
Maher, Brion S; Latendresse, Shawn; Vanyukov, Michael M (2018) Informing Prevention and Intervention Policy Using Genetic Studies of Resistance. Prev Sci 19:49-57
Latendresse, Shawn J; Musci, Rashelle; Maher, Brion S (2018) Critical Issues in the Inclusion of Genetic and Epigenetic Information in Prevention and Intervention Trials. Prev Sci 19:58-67
Musci, Rashelle J; Schlomer, Gabriel (2018) The Implications of Genetics for Prevention and Intervention Programming. Prev Sci 19:1-5
Rabinowitz, Jill A; Musci, Rashelle J; Milam, Adam J et al. (2018) The interplay between externalizing disorders polygenic risk scores and contextual factors on the development of marijuana use disorders. Drug Alcohol Depend 191:365-373
Musci, Rashelle J; Bettencourt, Amie F; Sisto, Danielle et al. (2018) Evaluating the genetic susceptibility to peer reported bullying behaviors. Psychiatry Res 263:193-198
Maher, Brion S (2015) Polygenic Scores in Epidemiology: Risk Prediction, Etiology, and Clinical Utility. Curr Epidemiol Rep 2:239-244