hearing loss is reasonably well understood, this is not the case for nicotine exposure. Our current PheWAS for CYP2A6 alleles identified association with hearing loss symptoms in nicotine-exposed elderly subjects. This result supports a harmful effect of smoking on auditory function mechanistically. Indeed, the CYP2A6 association with hearing loss highlights how nicotine metabolism is a relevant pathway in this pathological condition. Further information is provided by the allele identified: rs113288603 is associated with CYP2A6 expression in the brain (specifically in cerebellar hemisphere). In a published NMR GWAS8, rs113288603 was the most significant independent signal (pcond = 7.03 × 10−25) after conditioning for the overall top SNP rs56113850 (p = 5.77 × 10−86). As reported above and also in a previous study10, rs56113850 is associated with CYP2A6 hepatic expression, consistent with its association with urinary and serum NMR (i.e. the minor allele C is associated with increased expression and with increased NMR). A similar situation pertains for CYP2A6 rs12461964 (i.e., concordant 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
