Shared genetic factors contributed to significant phenotypic correlations between cigarette pack-years and cortical surface area and volume in the right caudal anterior cingulate cortex and right pars opercularis (prefrontal cortex) as well as subcortical volume in the left cerebellum cortex. These ROIs have been previously identified in a network related to the control of smoking behavior (O'Doherty et al. 2000; Breiter and Rosen 1999; Koob and Volkow 2010; Volkow et al. 2003). There are several genes were identified through prior genetic association studies that are also are likely to be expressed in these ROIs. For example, prior studies in humans report upregulation of nicotinic acetylcholine receptors (nAChRs) genes resulting from cigarette smoking in the prefrontal cortex, brainstem and cerebellum. Genes responsible for the nicotinic receptor subunits (CHRNA5, CHRNA3 and CHRNB4) alter receptor activity and sensitivity to nicotine. Variants of these genes have been associated with risk for nicotine dependence particularly during adulthood (Ducci et al. 2011; Wang et al. 2009).
