Large studies in this research field are, however, mostly lacking; some of the largest concern smoking traits. DNA methylation alteration extensively associates with smoking and is a plausible link between smoking and adverse health129. A large-scale EWAS of cigarette smoking in >15,500 participants identified thousands of methylation sites associated with smoking status, with different patterns between current and formers smokers130. A striking effect of tobacco smoking was observed in reducing the methylation of CpG sites located in the AHRR locus, which encodes the aryl hydrocarbon receptor repressor131. This association is one of the strongest and most consistently replicated epigenetic relationships for psychiatric traits so far; in fact, several algorithms have been developed to predict smoking status on the basis of epigenetic variation132. Different aspects of how tobacco smoking affects methylation changes have been explored, including the role of nicotine metabolism, the effect of prenatal exposure, and the risk of lung cancer in smokers133–135.
