Genetics of Nicotine Addiction

Abstract

Diseases associated with addiction to nicotine, the key reinforcing constituent of tobacco, remain the largest cause of preventable death worldwide. Although twin studies indicate a large genetic contribution to the variation in smoking‐related behaviours, the polymorphisms underlying this heritability remain largely unidentified. Candidate gene studies have investigated several pathways, but thus far only those few genetic loci identified in unbiased genome‐wide association studies have been consistently replicated; these are the direct targets of nicotine in the nervous system, the nicotinic acetylcholine receptor subunit genes CHRNA5–CHRNA3–CHRNB4 and the primary nicotine metabolism gene CYP2A6 . These variants may differ in their influences regarding different aspects of smoking behaviour, and their frequencies vary widely among different ethnic populations. Use of more‐targeted phenotypes including biomarkers of smoke exposure such as cotinine, nicotine's major metabolite, and exhaled carbon monoxide, may provide the key to detecting further genetic correlates of nicotine dependence and related diseases. Key Concepts: Variation in nicotine addiction‐related traits have large genetic components. Genetic studies of nicotine addiction seek to identify drug targets for smoking cessation treatment and to improve treatments using genotype‐based personalised medicine. Candidate gene studies have focussed on the nicotinic acetylcholine receptors and genes in the nicotine metabolism, dopaminergic, serotonergic, GABAergic, and opioid pathways, but few associations have been convincingly replicated. Unbiased genome‐wide studies have identified very few consistent genetic associations with smoking‐related phenotypes. A functional variant in the CHRNA5–CHRNA3–CHRNB4 gene cluster is robustly associated with multiple smoking behaviours and related disease risk. Functional variation in the CYP2A6 nicotine metabolism gene is associated with cigarette consumption and related disease risk. Genetic factors contributing to nicotine addiction vary by ethnic population. Genotype–environment and genotype–treatment interactions are important factors determining smoking initiation, dependence and cessation outcomes. Use of biomarkers and other endophenotypes may provide greater power to identify genetic correlates of nicotine dependence.