Rare variants in CHRNA4 have also been implicated as contributing to nicotine dependence risk. A rare missense variant allele in exon 5, R336C (rs56175056), which lowers the sensitivity of the α4 receptor to nicotine exposure,90 has been associated with increased risks of nicotine dependence and smoking-related diseases, including lung cancer, chronic obstructive pulmonary disease, peripheral artery disease and abdominal aortic aneurysms.91 Another rare variant in exon 5, P451L (rs55915440), was nominated for its association with decreased risk of nicotine dependence92 but not independently corroborated.91 rs2273500 is located 5.2 kb from R336C and 5.5 kb from P451L; neither rare variant was captured in our study owing to their frequencies.
