THE 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, tobacco smoking is responsible for approximately three million deaths world-wide, with an estimated 435,000 deaths in the USA alone. More than 98% of tobacco 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). We found a region near marker D10S42 on chromosome 10q22 that showed a significant linkage. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 adn D13S788. The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Most recently, an association study of the linked region on chromosome 9 strongly suggests that the tyrosine kinase receptor 2 gene (NTRK2) is involved with nicotine dependence.