Smoking-related genes and functional consequences

As the leading preventable cause of cancer and death, nicotine use and dependence have been the subject of a multitude of genetic studies in the past decade, ranging from candidate gene studies to genome-wide association studies (GWAS) to prospective studies. The genetics of nicotine addiction, smoking, and cancer are multifactorial, as would be expected from a complex behavior such as cigarette smoking. The combined heritability based on twin studies is estimated at 50-75 % (Li, Am J Med Sci 326(4): 168-73, 2003; Hall et al. Tob Control 11(2): 119-24, 2002; Lessov et al. Psychol Med 34(5): 865-79, 2004.; Lessov-Schlaggar et al. Int J Epidemiol 35(5): 1278-85, 2006; Maes et al. Psychol Med 34(7): 1251-61, 2004), with a large number of genes contributing to a small amount of risk individually. Some genes contribute to the quantity of nicotine used, while another set is associated with the duration of nicotine use, and yet another set is linked with severity of nicotine dependence. Associated "risky" genes comprise genes encoding for nicotinic acetylcholine receptor (nAChR) subunits, but also include genes like the bitter taste receptor. Still others have been associated with initiation and with success, or lack thereof, in cessation. In this chapter we review the current fi ndings in the genetics of smoking, focusing on those studies that have linked nicotinic acetylcholine receptors (nAChR) to nicotine addiction, and further discuss how mutations in these receptors alter their function.