Genetic manipulations in cell or animal models, as well as studies using tissue samples or cell lines, can be used to elucidate the functional impact of genetic variants. One example is the case of the CHRNA5-A3-B4 cluster on chromosome 15, encoding nicotinic acetylcholine receptor (nAChRs) subunits, which has been implicated as a susceptibility locus for nicotine addiction and lung cancer in numerous GWA studies. Even though a number of variants within the CHRNA5-A3-B4 cluster have been implicated in nicotine addiction, a rationale for how these receptor subunits may be mediating these phenotypes is currently lacking. For example, it is not known whether these genes are involved in initiation, progression or maintenance of nicotine dependence. Furthermore, whether the associations of this gene cluster with lung cancer and COPD is a direct or indirect effect via an influence on cigarette consumption remains to be clarified. Understanding the biological significance of the CHRNA5-A3-B4 receptor subunits and the functional significance of the variants implicated in this gene cluster will help interpret the observed associations.
