In the discovery PheWAS in the WHI nicotine-exposed sample, we observed a significant association between CYP2A6 rs113288603 and hearing loss. The minor allele T was associated with reduced symptoms, i.e., it was protective (p = 5.75 × 10−5; Table 1). To test whether the hearing-loss association was dependent on nicotine exposure, we analyzed the WHI nicotine-unexposed sample. No association was observed between CYP2A6 rs113288603 and hearing loss symptoms (p = 0.871) among unexposed subjects, and a significant difference was observed between nicotine-exposed and nicotine-unexposed results (pInteraction = 8.67 × 10−3; Fig. 1). To confirm the finding from the discovery PheWAS, we conducted an additional analysis in the LLFS cohort, where we observed a replication of the negative association between CYP2A6 rs113288603 and hearing loss symptoms in nicotine-exposed subjects (p = 0.098), and as with the discovery sample, no association was observed in the LLFS nicotine-unexposed sample (p = 0.524). A difference was observed when considering an interaction with nicotine exposure for the LLFS sample (nicotine-exposed vs. nicotine-unexposed; p = 0.097). Beyond rs113288603, we observed evidence for possible associations of rs56113850
