Tobacco use, primarily through cigarette smoking, is the largest cause of preventable mortality in the United States and the world. Other substance addictions cause added public health burdens. The overall objectives of this project are to identify genetic variants that alter risk for smoking and nicotine dependence, and to evaluate their role in determining risk for other substance dependence. In the cholinergic nicotinic receptor subunit gene cluster CHRNA5-CHRNA3-CHRNB4, two distinct groups of nicotine addiction risk variants have now been confirmed in multiple independent studies.
Aim 1 will examine these strong genetic findings using genotyped, community-based, longitudinal samples with smoking data. The goal is to determine the broader health implications and epidemiological profile of these risk variants. To further build on the confirmed findings in CHRNA5-CHRNA3-CHRNB4, in Aim 2 we will DNA sequence the larger region of strong linkage disequilibrium containing this cluster in both European-Americans and African-Americans to identify novel genetic variants. We will then genotype and test these variants for association with nicotine dependence in samples from both populations.
Aim 3 extends our study of smoking by integrating genotypic and smoking data across several large genome-wide association studies (GWAS). The goal is to identify additional genetic risk variants and gene-gene interactions in this powerful and unique combined sample.
In Aim 4 we will examine the relationships between loci identified for smoking and for addiction to other substances. By testing smoking risk loci for association with risk for other substance addiction, we can evaluate the common versus specific effects of these genes on susceptibility to substance dependence. Altogether, this project will further our understanding of the risks conferred by variation in established genes involved in smoking, and will allow us to uncover new genetic loci elsewhere in the genome that contribute to risk for smoking and associated morbidities.

Public Health Relevance

Smoking and nicotine addiction create profound public health burdens. Recent and rapid progress has begun to establish genetic loci that influence risk for smoking. Explaining more of the genetic architecture that underlies this extremely important public health problem will inform continued efforts to prevent and control smoking and other substance addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026911-04
Application #
8305010
Study Section
Special Emphasis Panel (ZRG1-HOP-G (02))
Program Officer
Pollock, Jonathan D
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$388,409
Indirect Cost
$132,877
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
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
Hancock, Dana B; Levy, Joshua L; Gaddis, Nathan C et al. (2015) Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1. Biol Psychiatry 78:474-84
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:
Ramnarine, Shelina; Zhang, Juan; Chen, Li-Shiun et al. (2015) When Does Choice of Accuracy Measure Alter Imputation Accuracy Assessments? PLoS One 10:e0137601
Agrawal, Arpana; Lynskey, Michael T; Kapoor, Manav et al. (2015) Are genetic variants for tobacco smoking associated with cannabis involvement? Drug Alcohol Depend 150:183-7
Grucza, Richard A; Plunk, Andrew D; Krauss, Melissa J et al. (2014) Probing the smoking-suicide association: do smoking policy interventions affect suicide risk? Nicotine Tob Res 16:1487-94
Culverhouse, Robert C; Johnson, Eric O; Breslau, Naomi et al. (2014) Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans. Addiction 109:814-22
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
Bierut, Laura Jean; Johnson, Eric O; Saccone, Nancy L (2014) A glimpse into the future - Personalized medicine for smoking cessation. Neuropharmacology 76 Pt B:592-9

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