Investigation of the genetic effect of 56 tobacco-smoking susceptibility genes on DNA methylation and RNA expression in human brain.

Although various susceptibility genes have been revealed to influence tobacco smoking, the underlying regulatory mechanisms between genetic variants and smoking are poorly understood. In this study, we investigated -expression quantitative trait loci (-eQTLs) and methylation quantitative trait loci (mQTLs) for 56 candidate smoking-linked genes using the BrainCloud cohort samples. An eQTL was revealed to significantly affect expression in the European sample and two mQTLs were respectively detected in CpG sites in and . Interestingly, we found for the first time that the minor allele of the single nucleotide polymorphism (SNP) rs3745277 located in (downstream of ) significantly decreased methylation at the CpG site for (cg25427638; = 5.31 × 10), reduced expression of ( = 0.03), and lowered the percentage of smokers (8.8% vs. 42.3%; Odds Ratio (OR) = 0.14, 95% Confidence Interval (CI): 0.02-0.62; = 4.47 × 10) in a dominant way for the same cohort sample. Taken together, our findings resulted from analyzing genetic variation, DNA methylation, mRNA expression, and smoking status together using the same participants revealed a regulatory mechanism linking mQTLs to the smoking phenotype. Moreover, we demonstrated the presence of different regulatory effects of low-frequency and common variants on mRNA expression and DNA methylation.