effect directions of hepatic expression and NMR). Conversely, rs113288603 appears to be different from these variants; it is not associated with CYP2A6 hepatic expression. This variant’s minor allele T correlates positively with CYP2A6 expression in cerebellar hemisphere and the effect direction is in the opposite direction with respect to serum and urinary NMR8, 9, i.e., increased CYP2A6 expression is associated with lower NMR. However, the association of rs113288603 with CYP2A6 expression in cerebellar hemisphere is in line with its protective effect on hearing loss symptoms (i.e., increased gene expression potentially associated with increased rate of nicotine metabolism in this tissue relevant to the auditory function). This indicates that the CYP2A6 gene may present different tissue-specific regulatory mechanisms. Rs56113850 and rs12461964 have strong effects on CYP2A6 hepatic regulation with consistent consequences on urinary and serum NMR; rs113288603 has a limited effect on hepatic regulation with reduced contribution on urinary and serum NMR (rs113288603 signal was genome-wide significant after adjusting the analysis for rs56113850). Conversely, this same variant, rs113288603, has a strong effect on CYP2A6 brain regulation (particularly in cerebellar hemisphere) and this is protective with respect to hearing loss symptoms. Rs56113850 and rs12461964 seem to provide a minimal contribution to CYP2A6
