The Role of Genetics in Nicotine Dependence: Mapping the Pathways from Genome to Syndrome

Abstract

Nicotine dependence continues to be a major public health problem worldwide and there is unequivocal evidence that genetics play a substantial role in its etiology. This review provides an overview of the evidence for genetic influences and recent advances in the field. Traditional quantitative genetics studies have revealed nicotine dependence is heritable and molecular genetics studies are providing increasing evidence that the genes responsible for nicotine's pharmacokinetics and pharmacodynamics are particularly important. Despite considerable progress, a number of significant complexities and challenges remain. These include determining the specificity of genetic influences and clarifying the role of interactive contributions. One promising strategy for addressing these issues is an intermediate phenotype approach that attempts to identify the intervening proximal mechanisms that confer differential genetic risk. Understanding these mechanisms may permit more precision in understanding genetic influences and may also identify novel targets for intervention or prevention.

Figure 1. A model of the role of genetics in nicotine dependence via alterations to nicotine’s pharmacokinetics and pharmacodynamics

Using continuous arrows, the pharmacokinetic pathways (blue) reflect the metabolic transformations of nicotine that determine its central and peripheral nervous system bioavailability and the pharmacodynamic pathways (green) reflect nicotine’s molecular pharmacological effects on nicotinic acetylcholinergic receptors (nAChRs) and other neurotransmitter systems. Candidate genes (orange) and their points of putative influence are depicted using dashed arrows. Note that this is a simplified model of nicotine’s pharmacokinetics and pharmacodynamics, and the candidate genes presented are illustrative examples, not an exhaustive list.