I request support through the K08 award to complete my transition from a clinical board-certified psychiatrist with prior research training in epidemiology to an independent translational researcher in genetic and environmental factors for smoking cessation. To achieve this goal, I need further training and experience in advanced genetics, cessation science, and longitudinal research methods, to enable me to conduct future prospective studies on genetics of smoking cessation. I will be guided by experts in the fields of advanced genetics (Drs. Laura Bierut, Alison Goate, John Rice, and Robi Mitra), cessation science (Drs. Timothy Baker and Gary Swan), and longitudinal research (Drs. Naomi Breslau, Eric Johnson, Laura Bierut, and Timothy Baker). The training goals will be advanced through the following proposed research on nicotine dependence which is a serious public health problem. Some genetic variants associated with nicotine dependence and smoking cessation have been identified with modern genetic methods, but account for only a small amount of genetic variance. Our preliminary results suggest comprehensive nicotine dependence phenotypes and prospective cessation measures have greater sensitivity to detect genetic associations. This study aims to fill gaps in the research literature by conducting (1) Genome Wide Association Study (GWAS) analyses of nicotine dependence using comprehensive novel phenotypes in two existing, complementary datasets (population vs. treatment sample), (2) GWAS analyses of prospective smoking cessation phenotype, and (3) a pilot longitudinal follow up study of nicotine dependence subjects to replicate the genetic findings of smoking cessation from study aim 2, and to examine identified genetic risks jointly with environmental, comorbid, and treatment factors. We hope to uncover novel genetic variants associated with refined phenotypic characteristics of nicotine dependence and smoking cessation. Genetic risks associated with smoking cessation may be different from those for nicotine dependence, and this distinction will be useful in translating genetic risk to outcome research. Knowledge of how genetic risks influence clinical outcomes and whether they are modified by treatment and comorbid disorder factors will not only clarify the etiology of nicotine dependence to create opportunity for prevention, but also provide needed evidence for individualized cessation treatments to increase the probability of successful quitting. This will be the foundation for future R01 applications for large scale, prospective studies of smoking cessation trials. In summary, by the end of this award, I will become an expert in psychiatric genetics with a focus on smoking cessation. Through my training in advanced genetic methods, cessation science, and longitudinal analyses, along with hands on experience in longitudinal data collection and analyses, I will establish a unique smoking cessation research program at Washington University and launch an independent career conducting large scale smoking cessation trials that will make important contributions to the treatment of nicotine dependence and related disorders.

Public Health Relevance

Nicotine Dependence and Smoking continue to be serious, global public health problems with high health and economic costs to this country despite prevention and treatments efforts. The proposed application aims to identify genetic and environmental factors that affect nicotine dependence and smoking cessation, which may suggest how treatments and environments can be modified to boost cessation success. This information is important for the development of better treatment strategies for nicotine dependence and tobacco-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DA030398-04
Application #
8700365
Study Section
AIDS Behavioral Research Subcommittee (NIDA)
Program Officer
Kimmel, Heather L
Project Start
2011-09-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Schwantes-An, Tae-Hwi; Zhang, Juan; Chen, Li-Shiun et al. (2016) Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts. Behav Genet 46:151-69
Olfson, E; Saccone, N L; Johnson, E O et al. (2016) Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Mol Psychiatry 21:601-7
Chen, Li-Shiun; Horton, Amy; Bierut, Laura (2016) Pathways to precision medicine in smoking cessation treatments. Neurosci Lett :
Chen, Li-Shiun; Baker, Timothy; Brownson, Ross C et al. (2016) Smoking Cessation and Electronic Cigarettes in Community Mental Health Centers: Patient and Provider Perspectives. Community Ment Health J :
Chen, Li-Shiun; Baker, Timothy; Hung, Rayjean J et al. (2016) Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis. EBioMedicine 11:219-226
Chen, Li-Shiun; Baker, Timothy B; Bierut, Laura J (2015) The value of control conditions for evaluating pharmacogenetic effects. Pharmacogenomics 16:2005-6
Chen, Li-Shiun; Hung, Rayjean J; Baker, Timothy et al. (2015) CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis. J Natl Cancer Inst 107:
Chen, Li-Shiun; Baker, Timothy B; Jorenby, Douglas et al. (2015) Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation. Drug Alcohol Depend 154:278-82
Chen, Li-Shiun; Baker, Timothy B; Piper, Megan E et al. (2014) Interplay of genetic risk (CHRNA5) and environmental risk (partner smoking) on cigarette smoking reduction. Drug Alcohol Depend 143:36-43
Chen, Li-Shiun; Bloom, A Joseph; Baker, Timothy B et al. (2014) Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6). Addiction 109:128-37

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