The questions of pleiotropy and effect moderation with comorbid psychiatric disorders regarding the CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster have not been previously studied, as this type of work involves comprehensive assessments of multiple phenotypes. Our results suggest no pleiotropy or moderation for nicotine dependence and examined psychiatric disorders. In contrast, there is strong evidence that these variants on chromosome 15 contribute to comorbid lung cancer and chronic obstructive pulmonary disease. There have been efforts to tease apart the potential pleiotropy between nicotine dependence, lung cancer, and COPD associated with this particular gene cluster and the results are controversial (Chanock and Hunter, 2008). Some studies have reported that the genetic association with lung cancer is completely or partially mediated by smoking or nicotine dependence, while others have reported a direct, non-mediated association between lung cancer and the gene cluster (Amos et al., 2008; Hung et al., 2008; Thorgeirsson et al., 2008; Whitfield et al., 2002).
