GENETICS OF SMOKING

Background

Smoking phenotypes. Nearly 40 years ago, R.A. Fisher (1958a; b) explored genetic factors in smoking and noted that concordance for smoking behavior was significantly higher in monozygotic (MZ) twins than in dizygotic (DZ) twins. Since some of the twins had not been reared together, the similarity between the twins could not be exclusively the result of environmental influences. These observations have been replicated many times over the years: Hughes, for instance, identified 18 twin studies in which concordance rates of smokers were consistently greater for MZ than for DZ twins, with a mean heritability estimates of 53% for tobacco use, ranging from 28% to 84% (Hughes, 1986, Table 1). Subsequent twin studies have demonstrated that genetic factors not only contribute to the initiation of smoking (Eaves & Eysenck, 1980; Hannah et al., 1984) but also influence age of onset of smoking and number of cigarettes smoked per day (Heath & Martin, 1993) as well as persistence of smoking and intensity of smoking-with significant genetic variation evident for both light and heavy smoking though not for moderate smoking (Carmelli et al., 1992; Heath & Martin, 1993). Along the same lines, odds ratios for nicotine-dependence in a second sibling of families where one sibling is nicotine-dependent have been found to range from 2.1 to 3.5, depending on the criteria used (Niu et al., 2000); similarly, in a study of adoptees who smoked, the odds ratio for current smoking in a full sibling was 3.2 and for heavy smoking it was 2.0 (Osler et al., 2001).

Smoking as a polygenic condition. Linkage analyses based on genome-wide markers have been employed to identify chromosomal locations that might contain genes for smoking (Bergen et al., 1999; Duggirala et al., 1999; Straub et al., 1999). While several susceptibility regions have been reported, there has not been much agreement across studies or even within studies at this point (Uhl et al., 2001). Among the concerns about the linkage approach is that individual gene effects for smoking may be too weak to be detected because single genes may account for only a small part of the total variance (Arinami et al., 2000). An alternative approach involving candidate genes associated with underlying mechanisms has also been tried and numerous putative genes have been identified (Boustead et al., 1997; Caparaso et al., 1997; Colerton et al., 1996; Comings et al., 1996; Garcia-Closas et al., 1997; Ishikawa et al., 1999; Lerman et al., 1998; Lerman et al., 1999 ; London et al., 1999; McKinney et al., 2000; Noble, 1994; Oscarson et al., 1998; Pianezza et al., 1998; Sabol & Hamer, 1999; Sabol et al., 1999; Schinka et al., 2002; Shields et al., 1998; Smith & Sachse, 2001; Spitz et al., 1998; Sullivan et al., 2001; Turgeon et al., 1995; Xu et al., 2002a; b; Zabetian et al., 2000). Replication and interpretation of these findings, however, has also been fraught with difficulty (Arinami et al., 2000; Munafo et al., 2001; Rossing, 1998; Walton et al., 2001; Watkins et al., 2000; Wonnacott, 2001). A variety of explanations have been offered, including inadequate specification of phenotypes (e.g., exclusive reliance on smoking status or clinical inventories), ascertainment bias (recruitment of subjects based on conditions other than smoking), insufficient power (sample size typically in the low hundreds), and an assortment of genotyping problems (often involving inadequate or inaccurate characterization of allelic variants). As an overall strategy to address these difficulties and to provide a resource for mutual assistance, the Nicotine Research Laboratory constituted a national Nicotine Research Consortium to draw on the expertise and capabilities of investigators specializing in phenotyping (SRI International), twin research and genetic analyses (Washington University), measured genetics (University of North Carolina), and nicotine metabolism (University of California San Francisco). This group of investigators also participates as the nicotine dependence subsection of the NIDA Genetics Research Consortium.

References

Arinami T, Ishiguro H, Onaivi ES (2000). Polymorphisms in genes involved in neurotransmission in relation to smoking. European Journal of Pharmacology 410:215-226.

Bergen AW, Korczak JF, Weissbecker KA, Goldsetin AM (1999). A genome-wide search for loci contributing to smoking and alcoholism. Genetic Epidemiology 17:S55-S60.

Boustead C, Taber H, Idle JR, Cholerton S (1997). CYP2D6 genotype and smoking behaviour in cigarette smokers. Pharmacogenetics 7:411-414.

Caparaso N, Lerman C, Main D, et al. (1997). The genetics of smoking: The dopamine receptor (DRD2) and transporter polymorphisms in a smoking cessation study. Proceedings of the American Association of Cancer Research 38:168.

Carmelli D, Swan GE, Robinette D, Fabsitz R (1992). Genetic influence on smoking — a study of male twins. NEJM 327:829-833.

Cholerton S, Boustead C, Taber H, Arpanahi A, Idle JR (1996). CYO2D6 genotypes in cigarette smokers and non-tobacco users. Pharmacogenetics 6:261-263.

Comings DE, Ferry L, Bradshaw-Robinson S, Burchette R, Chiu C, Muhleman D (1996). The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics 6:73-79.

Duggirala R, Almasy L, Biangero J (1999). Smoking behavior is under the influence of a major quantitative trait locus on human chromosome 5q. Genetic Epidemiology 17:S139-S144.

Eaves LJ, Eysenck HJ (1980). New approaches to the analysis of twin data and their application to smoking behavior. In: Eysenck HJ (Ed), The causes and effects of smoking, pp 140-314. London: Maurice Temple Smith.

Fisher RA (1958a). Cancer and smoking. Nature 182:596.

Fisher RA (1958b). Lung cancer and cigarettes. Nature 182:108

Garcia-Closas M, Caporaso N, Kelsey K, Christiani D (1997). Association between CYP1A1 polymorphism and smoking in a control population: implications for the study of genetic factors on cancer risk. Proceedings of the American Association of Cancer Researchers 38:211.

Hannah MC, Hopper JL, Mathews JD (1984). Twin concordance for a binary trait. II. Nested analysis of ever-smoking and ex-smoking traits and unnested analysis of a committed-smoking trait. American Journal of Human Genetics 37: 153-165.

Heath AC, Martin NG (1993). Genetic models for the natural history of smoking: Evidence for a genetic influence on smoking persistence. Addictive Behaviors 18:19-34.

Hughes JR (1986). Genetics of smoking: A brief review. Behavior Therapy 17:335-345.

Ishikawa H, Ohtsuki T, Ishiguro H, Yamakawa-Kobayashi K, Endo K, Lin YL, Yanagi H, Tsuchiya S, Kawata K, Hamaguchi H, Arinami T (1999). Association between serotonin transporter gene polymorphisms and smoking among Japanese males. Cancer Epidemiology: Biomarkers and Prevention 8: 831-833.

Lerman C, Caporaso NE, Audrain J, Main D, Bowman ED, Lockshin B, Boyd NR, Shields PG (1999). Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychology 18:14-20.

Lerman C, Caporaso N, Main D, Audrain J, Boyd NR (1998). Depression and self-medication with nicotine: The modifying influence of the dopamine D4 receptor gene. Health Psychology 17:56-62.

London SJ, Idle JR, Daly AK, Coetze GA (1999). Genetic variation of CYP2A6, smoking and risk of cancer. Lancet 353:898-899.

McKinney EF, Walton RT, Yudkin P, Fuller A, Haldar NA, Mant D, Murphy M, Welsh KI, Marshall SE (2000). Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics 10:483-491.

Munafo M, Johnstone E, Murphy M, Walton R (2001). New directions in the genetic mechanisms underlying nicotine addiction. Addiction Biology 6:109-117.

Niu T, Chen C, Ni J, Wang B, Fang Z, Shao H, Xu X (2000). Nicotine dependence and its familial aggregation in Chinese. International Journal of Epidemiology 29: 248-252.

Noble EP (1994). D2 dopamine receptor gene and cigarette smoking: A reward gene? Medical Hypotheses 42:257-260.

Oscarson M, Gullsten H, Rautio A, Bernal ML, Sinues B, Dahl ML, Stengard JH, Pelkonen O, Raunio H, and Ingelman-Sundberg M (1998). Genotyping of human cytochrome P450 2A6 (CYP2A6), nicotine C-oxidase. FEBS Letters 438:201-205.

Osler M, Holst C, Prescott E, Sorensen TI (2001). Influence of genes and family environment on adult smoking behavior assessed in an adoption study. Genetic Epidemiology 21:193-200

Pianezza ML, Sellers EM, Tyndale RF (1998). Nicotine metabolism defect reduces smoking Nature 393:750.

Rossing MA (1998). Genetic influences on smoking: Candidate genes. Environmental Health Perspectives 106:231-238.

Sabol SZ, Hamer DH (1999). An improved assay shows no association between the CYP2A6 gene and cigarette smoking behavior. Behavior Genetics 29:257-261.

Sabol SZ, Nelson ML, Fisher C, Gunzerath L, Brody CL, Hu S, Sirota LA, Marcus SE, Greenberg BD, Lucas FR, Benjamin J, Murphy DL, Hamer DH (1999). A genetic association for cigarette smoking behavior. Health Psychology 18:7-13.

Schinka JA, Town T, Abdullah L, Crawford FC, Ordorica PI, Francis E, Hughes P, Graves AB, Mortimer JA, Mullan M (2002). A functional polymorphism within the mu-opioid receptor gene and risk for abuse of alcohol and other substances. Molecular Psychiatry 7:224-228.

Shields PG, Lerman C, Audrain J, Bowman ED, Main D, Boyd NR, Caporaso NE (1998). Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians. Cancer Epidemiology: Biomarkers and Prevention 7:453-458.

Smith G, Sachse C (2001). A role for CYP2D6 in nicotine metabolism? Psycoloquy 12:5.

Spitz MR, Shi H, Yang F, Hudmon KS, Jiang H, Chamberlain RM, Amos CI, Wan Y, Cinciripini P, Hong WK, Wu X (1998). Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients. Journal of the National Cancer Institute 90:358-363.

Straub RE, Sullivan PF, Ma Y, Myakishev MV, Harris-Kerr C, Wormley B, Kadambi B, Sadek H, Silverman MA, Webb BT, Neale MC, Bulik CM, Joyce PR, Kendler KS (1999). Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17, 18 merit further study. Molecular Psychiatry 4: 129-144.

Sullivan PF, Jiang Y, Neale MC, Kendler KS, Straub RE (2001). Association of the tryptophan hydroxylase gene with smoking initiation but not progression to nicotine dependence. American Journal of Medical Genetics 105:479-484.

Turgeon J, Labbe L, Lefez C, Lebel M (1995). Debrisoquine metabolic ratio (DMR) distribution differs among smokers and non-smokers. American Society of Clinical Pharmacology and Therapeutics 57:150.

Uhl GR, Liu Q-R, Walther D, Hess, Naiman D (2001). Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. American Journal of Human Genetics 69:1290-1300.

Walton R, Johnstone E, Munafo M, Neville M, Griffiths S (2001). Genetic clues to the molecular basis of tobacco addiction and progress towards personalized therapy. TRENDS in Molecular Medicine 7:70-76.

Watkins S, Koob GF, Markou A (2000). Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine and Tobacco Research 2:19-37.

Wonnacott S (2001). Nicotinic receptors in relation to nicotine addiction. Psycoloquy 12:6.

Xu C, Goodz S, Sellers EM, Tyndale RF (2002a). CYP2A6 genetic variation and potential consequences. Advanced Drug Delivery Reviews 54:1245-56.

Xu C, Rao YS, Xu B, Hoffman E, Jones J, Sellers EM, Tyndale RF (2002b). An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. Biochemical and Biophysical Research Communications 290:318-324.

Zabetian CP, Gelernter J, Cubells JF (2000). Functional variants at CYP2A6: new genotyping methods, population genetics, and relevance to studies of tobacco dependence. American Journal of Medical Genetics 96:638-645.

Back to Lines of Research