GENETICS OF NICOTINE DEPENDENCE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cigarette smoking is a highly prevalent and harmful behavior. Annually, tobacoo smoking is responsible for approximately three million deaths world-wide, with an estimated 435,000 deaths in the USA alone. More than 98% of tobacoo users are cigarette smokers. Although a minority of tobacco smokers do not smoke daily, most do and are physically dependent on nicotine, the primary addictive component of cigarette smoke. Like all substance-dependence disorders, nicotine dependence has a substantial heritable component. Over the last few decades, many large-sample twin studies have concluded that genetics contributes to the risk of becoming a regualr smoker. DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). In a study of 602 nuclear families of African- or European-American ancestry, we found evidence for the involvement of DDC in the susceptibility to ND and, further, racial specificity of its impact. We also tested six single nucleotide polymorphisms (SNPs) in the alpha 4 subunit gene (CHRNA4) and four SNPs in the beta 2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors for association with nicotine dependence, and found convincing evidence for the involvement of the nAChR alpha 4 subunit, but not of the nAChR beta 2 subunit, in nicotine addiction. Finally, we found association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene with vulnerability to nicotine dependence.