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 #
5R01DA018432-02
Application #
7232735
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Caulder, Mark
Project Start
2006-06-01
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$766,884
Indirect Cost
Name
University of Connecticut
Department
Psychiatry
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Smith, Andrew H; Ovesen, Peter L; Skeldal, Sune et al. (2018) Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. Alcohol Clin Exp Res 42:2337-2348
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus. Mol Psychiatry 23:154-160
Polimanti, R; Kaufman, J; Zhao, H et al. (2018) Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers. Acta Psychiatr Scand 137:148-156
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Polimanti, Renato; Gelernter, Joel (2018) ADH1B: From alcoholism, natural selection, and cancer to the human phenome. Am J Med Genet B Neuropsychiatr Genet 177:113-125
Zhou, Hang; Cheng, Zhongshan; Bass, Nicholas et al. (2018) Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression. Transl Psychiatry 8:208
Montalvo-Ortiz, Janitza L; Zhou, Hang; D'Andrea, Ivana et al. (2018) Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response. Mol Psychiatry 23:2277-2286
Cheng, Zhongshan; Zhou, Hang; Sherva, Richard et al. (2018) Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. Biol Psychiatry 84:762-770
Hancock, D B; Guo, Y; Reginsson, G W et al. (2018) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry 23:1-9
Cabana-Domínguez, Judit; Arenas, Concepció; Cormand, Bru et al. (2018) MiR-9, miR-153 and miR-124 are down-regulated by acute exposure to cocaine in a dopaminergic cell model and may contribute to cocaine dependence. Transl Psychiatry 8:173

Showing the most recent 10 out of 74 publications