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Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior

Molecular Psychiatry volume 5, pages 181–188 (2000)Cite this article

Abstract

Cigarette smoking behavior is influenced by both personality traits and inherited factors. Previous research showed that neuroticism—a broad personality domain that includes anxiety, depression, impulsiveness and vulnerability—increases the risk of being a smoker, primarily because of difficulty in quitting. Neuroticism has also been associated with the 5-HTTLPR, a functional polymorphism in the promoter for the serotonin transporter gene. We used population and family-based methods to analyze the joint effects of the 5-HTTLPR and neuroticism on smoking behavior in a population of 759 never, current, and former smokers, all members of sib-pairs. Our main finding is that smoking behavior is influenced by an interaction between neuroticism and 5-HTTLPR genotype. Specifically, neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed 5-HTTLPR-S genotypes, but not in those with the more highly expressed 5-HTTLPR-L genotype. Individuals with both a 5-HTTLPR-S genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data, if replicated, suggest that smoking behavior is more strongly influenced by the combination of the serotonin transporter gene and neuroticism than by either factor alone, and that personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs.

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References

  1. Sachs DP, Leischow SJ . Pharmacologic approaches to smoking cessation Clin Chest Med 1991; 12: 769–791

    CAS  PubMed  Google Scholar 

  2. Shiffman S . Smoking cessation treatment: any progress? J Consult Clin Psychol 1993; 61: 718–722

    Article  CAS  Google Scholar 

  3. Barefoot JC, Smith RH, Dahlstrom WG, Williams RB . Personality predictors of smoking behavior in a sample of physicians Psychology and Health 1989; 3: 37–43

    Article  Google Scholar 

  4. Patton D, Barnes GE, Murray RP . Personality characteristics of smokers and ex-smokers Personality and Individual Differences 1993; 15: 653–664

    Article  Google Scholar 

  5. Lipkus IM, Barefoot JC, Williams RB, Siegler IC . Personality measures as predictors of smoking initiation and cessation in the UNC Alumni Heart Study Health Psychol 1994; 13: 149–155

    Article  CAS  Google Scholar 

  6. Heath AC, Madden PAF, Slutske WS, Martin NG . Personality and the inheritance of smoking behavior: a genetic perspective Behavior Genet 1995; 25: 103–117

    Article  CAS  Google Scholar 

  7. Carmelli D, Swan GE, Robinette D, Fabsitz R . Genetic influence on smoking—a study of male twins N Engl J Med 1992; 327: 829–833

    Article  CAS  Google Scholar 

  8. Heath AC, Madden PG . Genetic influences on smoking behavior. In: Turner JR, Cardon LR, Hewitt JK (eds) Behavior Genetic Approaches in Behavioral Medicine Plenum: New York 1995; pp37–48

    Google Scholar 

  9. Heath AC, Martin N . Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence Addict Behav 1993; 18: 19–34

    Article  CAS  Google Scholar 

  10. Costa PT Jr, McCrae RR . The Revised NEO Personality Inventory (NEO-PI-R) and NEO Five Inventory (NEO-FFI) Professional Manual Psychological Assessment Resources: Odessa, FL 1992

    Google Scholar 

  11. McCrae RR, Costa PT Jr, Bosse R . Anxiety, extraversion and smoking Br J Soc Clin Psychol 1978; 17: 269–273

    Article  CAS  Google Scholar 

  12. Breslau N, Kilbey MM, Andreski P . Vulnerability to psychopathology in nicotine-dependent smokers: an epidemiologic study of young adults Am J Psychiatry 1993; 150: 941–946

    Article  CAS  Google Scholar 

  13. Gilbert DG . Personality, psychopathology, tobacco use, and individual differences in effects of nicotine. In: Baker KP, Seltzer H (eds) Smoking: Individual Differences, Psychopathology, and Emotion Taylor & Francis: Washington, DC 1995; pp149–176

    Google Scholar 

  14. Anda RF, Williamson DF, Escobedo LG, Mast EE, Giovino GA, Remington PL . Depression and the dynamics of smoking. A national perspective Jama 1990; 264: 1541–1545

    Article  CAS  Google Scholar 

  15. Borrelli B, Niaura R, Keuthen NJ, Goldstein MG, DePue D, Murphy C et al. Development of major depressive disorder during smoking-cessation treatment J Clin Psychiatry 1996; 57: 534–538

    Article  CAS  Google Scholar 

  16. Covey LS, Glassman AH, Stetner F . Depression and depressive symptoms in smoking cessation Compr Psychiatry 1990; 31: 350–354

    Article  CAS  Google Scholar 

  17. Glassman AH, Helzer JE, Covey LS, Cottler LB, Stetner F, Tipp JE et al. Smoking, smoking cessation, and major depression Jama 1990; 264: 1546–1549

    Article  CAS  Google Scholar 

  18. Breslau N, Kilbey M, Andreski P . Nicotine dependence, major depression, and anxiety in young adults Arch Gen Psychiatry 1991; 48: 1069–1074

    Article  CAS  Google Scholar 

  19. Breslau N, Kilbey MM, Andreski P . Nicotine dependence and major depression. New evidence from a prospective investigation Arch Gen Psychiatry 1993; 50: 31–35

    Article  CAS  Google Scholar 

  20. Kendler KS, Neale MC, MacLean CJ, Heath AC, Eaves LJ, Kessler RC . Smoking and major depression: a causal analysis Arch Gen Psychiatry 1993; 50: 36–43

    Article  CAS  Google Scholar 

  21. Covey LS, Glassman AH, Stetner F . Major depression following smoking cessation Am J Psychiatry 1997; 154: 263–265

    Article  CAS  Google Scholar 

  22. Covey LS, Glassman AH, Stetner F . Cigarette smoking and major depression J Addict Dis 1998; 17: 35–46

    Article  CAS  Google Scholar 

  23. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL et al. Organization of the human serotonin transporter gene J Neural Transm Gen Sect 1994; 95: 157–162

    Article  CAS  Google Scholar 

  24. Heils A, Mossner R, Lesch KP . The human serotonin transporter gene polymorphism—basic research and clinical implications J Neural Transm 1997; 104: 1005–1014

    Article  CAS  Google Scholar 

  25. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression J Neurochem 1996; 66: 2621–2624

    Article  CAS  Google Scholar 

  26. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region Science 1996; 274: 1527–1531

    Article  CAS  Google Scholar 

  27. Little KY, McLaughlin DP, Zhang L, Livermore CS, Dalack GW, McFinton PR et al. Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels Am J Psychiatry 1998; 155: 207–213

    Article  CAS  Google Scholar 

  28. Greenberg BD, Qian L, Lucas FR, Hu S, Sirota LA, Benjamin J et al. Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. (submitted)

  29. Ricketts MH, Hamer RM, Sage JI, Manowitz P, Feng F, Menza MA . Association of a serotonin transporter gene promoter polymorphism with harm avoidance behaviour in an elderly population Psychiatr Genet 1998; 8: 41–44

    Article  CAS  Google Scholar 

  30. Katsuragi S, Kunugi H, Sano A, Tsutsumi T, Isogawa K, Nanko S et al. Association between serotonin transporter gene polymorphism and anxiety-related traits Biol Psychiatry 1999; 45: 368–370

    Article  CAS  Google Scholar 

  31. Murakami F, Shimomura T, Kotani K, Ikawa S, Nanba E, Adachi K . Anxiety traits associated with a polymorphism in the serotonin transporter gene regulatory region in the Japanese J Hum Genet 1999; 44: 15–17

    Article  CAS  Google Scholar 

  32. Osher Y, Hamer DH, Benjamin J . Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs Mol Psychiatry 2000; 5: 216–219

    Article  CAS  Google Scholar 

  33. Ebstein RP, Gritsenko I, Nemanov L, Frisch A, Osher Y, Belmaker RH . No association between the serotonin transporter gene regulatory region polymorphism and the tridimensional personality questionnaire (TPQ) temperament of harm avoidance Mol Psychiatry 1997; 2: 224–226

    Article  CAS  Google Scholar 

  34. Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B et al. An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms Mol Psychiatry 1998; 3: 449–451

    Article  CAS  Google Scholar 

  35. Lerman C, Sheilds PG, Audrain J, Main D, Cobb B, Boyd NR et al. The role of the serotonin transporter gene in cigarette smoking Cancer Epidemiol Biomarkers Prev 1998; 7: 253–255

    CAS  PubMed  Google Scholar 

  36. Zar JH . Biostatistical Analysis Prentice Hall: Upper Saddle River, NJ 1996

    Google Scholar 

  37. Lerman C, Caporaso NE, Audrain J, Main D, Cobb B, Boyd NR et al. Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence Mol Psychiatry 2000; 5: 189–192

    Article  CAS  Google Scholar 

  38. Cornelius JR, Salloum IM, Ehler JG, Jarrett PJ, Cornelius MD, Black A et al. Double-blind fluoxetine in depressed alcoholic smokers Psychopharmacol Bull 1997; 33: 165–170

    CAS  PubMed  Google Scholar 

  39. Niaura R, Goldstein M, Spring B et al. Fluoxetine for smoking cessations: a multicenter randomized double blind dose response study Presentation to Society of Behavioral Medicine, San Francisco 1997

    Google Scholar 

  40. Pontieri FE, Tanda G, Orzi F, Di Chiara G . Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs Nature 1996; 382: 255–257

    Article  CAS  Google Scholar 

  41. Epping-Jordan MP, Watkins SS, Koob GF, Markou A . Dramatic decreases in brain reward function during nicotine withdrawal Nature 1998; 393: 76–79

    Article  CAS  Google Scholar 

  42. Parsons LH, Justice JB Jr . Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis Brain Res 1993; 606: 195–199

    Article  CAS  Google Scholar 

  43. Parsons LH, Weiss F, Koob GF . Serotonin 1b receptor stimulation enhances dopamine-mediated reinforcement Psychopharmacol (Berl) 1996; 128: 150–160

    Article  CAS  Google Scholar 

  44. Rocha BA, Scearce-Levie K, Lucas JJ, Hiroi N, Castanon N, Crabbe JC et al. Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor Nature 1998; 393: 175–178

    Article  CAS  Google Scholar 

  45. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC et al. A comparison of sustained-release bupropion and placebo for smoking cessation N Engl J Med 1997; 337: 1195–1202

    Article  CAS  Google Scholar 

  46. Hall SM, Munoz RF, Reus VI . Cognitive-behavioral intervention increases abstinence rates for depressive-history smokers J Consult Clin Psychol 1994; 62: 141–146

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the participants who made this research possible. We are grateful to Jonathan Benjamin, Frank Lucas, Angela Pattatucci, Kirsten Blount, Gabriela Cora-Locatelli, and the staff at the NIH Clinical Center for help with subject recruitment, data collection and phlebotomy.

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Authors and Affiliations

  1. Laboratory of Biochemistry, National Cancer Institute, Bethesda, 20892, MD, USA

    S Hu, C L Brody, C Fisher, L Gunzerath, M L Nelson, S Z Sabol, L A Sirota & D H Hamer

  2. Oral Disease Prevention, Risk Factors, and Molecular Epidemiology Branch, National Institute of Dental Research, Bethesda, 20892, MD, USA

    S E Marcus

  3. Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, 20892, MD, USA

    B D Greenberg & D L Murphy

Authors
  1. S Hu
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  2. C L Brody
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  3. C Fisher
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  5. M L Nelson
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  11. D H Hamer
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Correspondence to D H Hamer.

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Hu, S., Brody, C., Fisher, C. et al. Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior. Mol Psychiatry 5, 181–188 (2000). https://doi.org/10.1038/sj.mp.4000690

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  • DOI: https://doi.org/10.1038/sj.mp.4000690

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