In conclusion, our PheWAS identified novel evidence supporting the role of CYP2A6 variation as an important mediator of at least one smoking consequence. In particular, our data indicate that genetic variation in the nicotine metabolism pathway can mediate the effect of smoking on age-related hearing loss. Our available sample size was rather limited; we predict, based on the likely link of this variant to the biology of quantitative nicotine exposure, that with better sample sizes, the range of medical consequences of nicotine use associated to this variant will grow. Hearing loss in the elderly population is associated with reduced quality of life and impaired psychological and motor skills that can lead to social isolation and depression31. A better understanding of age-related hearing loss may permit us to develop more effective preventive strategies and therapeutic approaches that can improve the quality of life of the growing elderly population. Additionally, knowledge of this genotype could identify smokers who should be evaluated for possible hearing loss, regardless of whether or not they report symptoms; although human subject studies will be required to ascertain
