This is a revised collaborative R01 proposal to study the genetics of cocaine dependence (CD) and related phenotypes, using a multifaceted approach. An important genetic contribution to risk for CD and related phenotypes is supported by clinical genetic data and by our first round of linkage results. The major purpose of this proposal is to identify specific risk alleles at loci predisposing to CD and related traits. The goals are to collect a set of >2000 CD cases and >2000 carefully ascertained population controls, and to recruit additional small nuclear families (SNFs) through affected cases, when possible. The resulting sample based on CD affection will have sufficient power to identify linkage disequilibrium with trait under reasonable assumptions of genetic heterogeneity. The clinical work will take place at five university-based programs in CT (Univ. of CT and Yale Univ.), MD (Johns Hopkins Univ.), PA (Univ. of PA), and SC (Medical Univ. of SC), and the laboratory and statistical work will be performed at Yale, Boston Univ. School of Medicine, and the Southwest Foundation for Biomedical Research. Affection will be defined according to DSM-IV diagnostic criteria, ascertained using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). This computerized instrument was developed in the previous grant period and has been shown to yield reliable diagnoses. We have implemented an extensive program to assure the quality of the detailed set of clinical data collected. This will continue the first large-scale study of CD gene mapping. Results from the first iteration of the project, in terms of subject recruitment and characterization and data analysis, support our ability to complete this ambitious research program successfully. This research program will also create an extensive resource for use by future investigators. The project will build on the successes of the first five-year SNF gene mapping project led by Drs. Gelernter and Kranzler (which has already identified several genomic """"""""regions of interest"""""""" for cocaine-related traits). The project will also contribute to a substantial increase in our understanding of the mechanisms of CD, and may lead to new approaches to the prevention and treatment of this pervasive societal problem. Public Health Relevance: This study will help to identify specific gene variants that contribute to the risk of cocaine and other drug dependence. Knowledge of the gene variants will help to identify people at greatest risk of developing the disorder, thereby improving prevention efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018432-05
Application #
7802981
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Caulder, Mark
Project Start
2006-06-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$327,400
Indirect Cost
Name
University of Connecticut
Department
Psychiatry
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Wang, Qian; Polimanti, Renato; Kranzler, Henry R et al. (2017) Genetic factor common to schizophrenia and HIV infection is associated with risky sexual behavior: antagonistic vs. synergistic pleiotropic SNPs enriched for distinctly different biological functions. Hum Genet 136:75-83
Smith, A H; Jensen, K P; Li, J et al. (2017) Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1. Mol Psychiatry 22:346-352
Polimanti, Renato; Gelernter, Joel (2017) ADH1B: From alcoholism, natural selection, and cancer to the human phenome. Am J Med Genet B Neuropsychiatr Genet :
Agrawal, A; Chou, Y-L; Carey, C E et al. (2017) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry :
Polimanti, Renato; Wang, Qian; Meda, Shashwath A et al. (2017) The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene. Neuropsychopharmacology 42:598-605
Polimanti, Renato; Meda, Shashwath A; Pearlson, Godfrey D et al. (2017) S100A10 identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours. J Psychiatry Neurosci 42:252-261
Yang, Bao-Zhu; Han, Shizhong; Kranzler, Henry R et al. (2017) Sex-specific linkage scans in opioid dependence. Am J Med Genet B Neuropsychiatr Genet 174:261-268
Hancock, D B; Guo, Y; Reginsson, G W et al. (2017) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry :
Polimanti, Renato; Zhang, Huiping; Smith, Andrew H et al. (2017) Genome-wide association study of body mass index in subjects with alcohol dependence. Addict Biol 22:535-549
Sherva, Richard; Wang, Qian; Kranzler, Henry et al. (2016) Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks. JAMA Psychiatry 73:472-80

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