3 The Nicotine-Dependence Phenotype: Translating Theoretical Perspectives and Extant Data into Recommendations for Genetic Mapping

The search for a possible genetic basis for nicotine dependence requires constructs that serve as a link between genes and behavior. Common existing measures of nicotine dependence are highly heritable and have high predictive validity for smoking outcomes yet lack specifi city relative to the underlying biological mechanisms that could inform future genetic research. This chapter examines theoretical issues in establishing nicotine-dependence phenotypes, including ■ Distal measures of nicotine dependence, such as the Fagerström tests, the Diagnostic and Statistical Manual of Mental Disorders, and others, focusing on mature nicotine dependence ■ Newer multidimensional measures of nicotine dependence, such as the Nicotine Dependence Syndrome Scale and the Wisconsin Inventory of Smoking Dependence Motives, examining motivational factors leading to dependence ■ Endophenotypes and transitional phenotypes, measuring quantities before and after nicotine exposure, respectively, that may potentially form a causal path between specifi c genetic actions and measures of nicotine dependence, including cognitive, affective, and craving factors Further study is needed to establish the validity of such endophenotypes and transitional phenotypes for upstream measures of nicotine dependence and their relationship with genetic and gene-environment infl uences, which, in turn, may support further research on the impact of such infl uences on smoking outcomes and behavior