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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-HOP-V (60))
Program Officer
Rutter, Joni
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
Melroy, Whitney E; Stephens, Sarah H; Sakai, Joseph T et al. (2014) Examination of genetic variation in GABRA2 with conduct disorder and alcohol abuse and dependence in a longitudinal study. Behav Genet 44:356-67
Hartman, Christie; Hopfer, Christian; Corley, Robin et al. (2013) Using Cloninger's temperament scales to predict substance-related behaviors in adolescents: a prospective longitudinal study. Am J Addict 22:246-51
Stephens, Sarah H; Hartz, Sarah M; Hoft, Nicole R et al. (2013) Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Genet Epidemiol 37:846-59
Kamens, H M; Corley, R P; McQueen, M B et al. (2013) Nominal association with CHRNA4 variants and nicotine dependence. Genes Brain Behav 12:297-304
Palmer, Rohan H C; Knopik, Valerie S; Rhee, Soo Hyun et al. (2013) Prospective effects of adolescent indicators of behavioral disinhibition on DSM-IV alcohol, tobacco, and illicit drug dependence in young adulthood. Addict Behav 38:2415-21
Thurstone, Christian; Salomonsen-Sautel, Stacy; Mikulich-Gilbertson, Susan K et al. (2013) Prevalence and predictors of injection drug use and risky sexual behaviors among adolescents in substance treatment. Am J Addict 22:558-65
Hopfer, Christian; Salomonsen-Sautel, Stacy; Mikulich-Gilbertson, Susan et al. (2013) Conduct disorder and initiation of substance use: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 52:511-518.e4
Palmer, R H C; Young, S E; Corley, R P et al. (2013) Stability and change of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis DSM-IV dependence symptoms. Behav Genet 43:374-85
Stephens, Sarah H; Hoft, Nicole R; Schlaepfer, Isabel R et al. (2012) Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. Behav Genet 42:402-14
Haberstick, Brett C; Zeiger, Joanna S; Corley, Robin P et al. (2011) Common and drug-specific genetic influences on subjective effects to alcohol, tobacco and marijuana use. Addiction 106:215-24

Showing the most recent 10 out of 20 publications