1. ¹Research Laboratory, Sara Herzog Memorial Hospital, Jerusalem, Israel
2. ²Neurobiology Program, Faculty of Medicine, Hebrew University, Jerusalem, Israel
3. ³Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
4. ⁴Department of Psychology, Hebrew University, Jerusalem, Israel

Correspondence: Professor B Lerer, Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem 91120, Israel. E-mail: lerer@cc.huji.ac.il

⁵These authors contributed equally to this work.

Received 21 December 2005; Revised 27 March 2006; Accepted 24 May 2006; Published online 13 June 2006.

Abstract

Cigarette smoking is a complex behavioral phenotype to which environmental, psychological and genetic factors contribute. The purpose of this study was to investigate these multifactorial effects with a specific focus on young women and on genes that encode serotonin (5-HT) receptors and the 5-HT transporter. A case–control sample of female Israeli college students provided comprehensive background data and details of cigarette smoking and completed a battery of psychological instruments. They were divided into smoking initiators (SI, n=242) or non-initiators (NI, n=148); SI were further subdivided into high (HND, n=127) and low nicotine-dependent smokers (LND, n=115) on the basis of their scores on the Fagerstrom Tolerance Questionnaire (FTQ). Single-nucleotide polymorphisms (SNPs) in five serotonin receptor genes (HTR1A, HTR1B, HTR2A, HTR2C and HTR6) and the 5-HT transporter-linked polymorphic region (5-HTTLPR) were genotyped. In a logistic regression model for SI (²=117.90, P=1.6 10^-19, Nagelkerke R²=0.42), novelty seeking (odds ratio (OR)=1.134, P=0.00009) was a significant risk factor. A five SNP CACCC haplotype in HTR6 was a strong protective factor against SI (OR=0.26; P=0.007). The interaction of HTR6-C276T genotype and lifetime traumatic experience contributed strongly to the risk of SI (OR=13.88, P=0.0001). Specifically, subjects homozygous for the HTR6-C276T C allele showed significantly increased risk of SI if they had experienced trauma. Although significant (²=42.85, P=1.00 10^-7), the best-fitting model for ND was less predictive than the model for SI (Nagelkerke R²=0.24). HTR1B-G861C GG genotype (OR=2.29, P=0.01) was a significant risk factor for HND. Further studies should consider the interactive contribution of life events and relevant gene variants to cigarette smoking and other complex behavioral traits.