have been identified and confirmed by multiple independent studies. The best replicated so far are risk alleles located in the CHRNA3–CHRNA5–CHRNB4 gene cluster that were associated with smoking behaviors (e.g., cigarettes per day) and smoking-associated diseases (e.g., lung cancer)5–7. Beyond this locus, another relevant gene is CYP2A6 (Cytochrome P450 Family 2 Subfamily A Member 6). Its protein product is involved in the nicotine metabolic pathway and its functional alleles have large effects on an index of CYP2A6 activity, the nicotine metabolite ratio (NMR)8–10, explaining a strikingly large fraction of the variance (up to 31%)8. It also has numerous other metabolic functions11. In our previous PheWAS for CHRNA3–CHRNA5–CHRNB4 risk alleles, we confirmed the association for smoking behaviors and known smoking consequences (e.g., lung cancer and asthma) and identified potential phenotypic associations related to human behaviors and lipid metabolism12.
