Cigarette smoking is the single largest preventable source of morbidity and mortality in North America and Europe. Twin and adoption studies indicate that a majority of risk for nicotine dependence (ND) is genetic. A genome-wide association (WGA) study of cigarettes per day (CPD), as a quantitative trait, was conducted with ~ 7500 individuals of European origin. Genotyping was done with Affymetrix 500K chips. A SNP in the alpha 3 nicotinic receptor subunit gene (CHRNA3) was associated with CPD as a quantitative trait (p = 0.00007). Analyses of CPD in a case-control mode (cases defined as smoking >25 CPD versus controls <5 CPD), was done in a second European-origin population of ~ 6200 controls and ~ 1740 cases, genotyped at ~ 6000 SNPs. In this second population, a CHRNA3 SNP was strongly associated with CPD (p = 0.0000026, odds ratio 1.30, 95% CI 1.17-1.48). These results are similar to a case-control study of ND by Saccone et al (2007), who reported association of several CHRNA3 SNPs (0.0003

Public Health Relevance

This research proposes to study DNA variations in genes which produce brain binding proteins for nicotine. These binding proteins are involved in the development of nicotine addiction. Understanding the function consequences of these DNA variations will provide direction in developing new medications for nicotine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025201-04
Application #
8214668
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Caulder, Mark
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$340,307
Indirect Cost
$124,239
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Toledo, Jon B; Bjerke, Maria; Chen, Kewei et al. (2015) Memory, executive, and multidomain subtle cognitive impairment: clinical and biomarker findings. Neurology 85:144-53
Doyle, Glenn A; Chou, Andrew D; Saung, Wint Thu et al. (2014) Identification of CHRNA5 rare variants in African-American heavy smokers. Psychiatr Genet 24:102-9
Clarke, Toni-Kim; Crist, Richard C; Kampman, Kyle M et al. (2013) Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine. Neurosci Lett 542:71-5
Berrettini, W H; Doyle, G A (2012) The CHRNA5-A3-B4 gene cluster in nicotine addiction. Mol Psychiatry 17:856-66
Kuryatov, Alexander; Berrettini, Wade; Lindstrom, Jon (2011) Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)₂α5 AChR function. Mol Pharmacol 79:119-25
Doyle, Glenn A; Wang, Min-Jung; Chou, Andrew D et al. (2011) In vitro and ex vivo analysis of CHRNA3 and CHRNA5 haplotype expression. PLoS One 6:e23373
Liu, Jason Z; Tozzi, Federica; Waterworth, Dawn M et al. (2010) Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 42:436-40