1. ¹Center for Health Sciences, SRI International, Menlo Park, CA, USA
2. ²Department of Preventative Medicine, University of Southern California, Pasadena, CA, USA
3. ³Artificial Intelligence Center, SRI International Menlo Park, CA
4. ⁴Department of Psychiatry, Washington University, St Louis, MO, USA
5. ⁵Center for Health Studies, Group Health Cooperative, Seattle, WA, USA
6. ⁶Oregon Research Institute, Eugene, OR, USA
7. ⁷Department of Neuroscience, Centre for Addiction and Mental Health and Department of Pharmacology, University of Toronto, Toronto, ON, USA
8. ⁸Departments of Medicine, Psychiatry and BioPharmaceutical Sciences, University of California at San Francisco, San Francisco, CA, USA
9. ⁹Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: Dr AW Bergen, Molecular Genetics Program, Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA. Tel: +1 650 859 4618; Fax: +1 650 859 5099; E-mail: andrew.bergen@sri.com

Received 11 December 2008; Revised 22 April 2009; Accepted 24 April 2009; Published online 3 June 2009.

Abstract

We utilized a cohort of 828 treatment-seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent's smoking behavior. A total of 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex, and study site. SNP P-values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3, and NR4A2 SNPs with adjusted P-values <0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic, and literature analyses. Each independent signal among the top-ranked SNPs accounted for 1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo, and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene–gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever-smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.