AUTHOR=Yang Zhongli , Yang Jiekun , Mao Ying , Li Ming D. 

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

JOURNAL=Frontiers in Psychiatry

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.924062

DOI=10.3389/fpsyt.2022.924062

ISSN=1664-0640

ABSTRACT=<p>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 <italic>cis</italic>-expression quantitative trait loci (<italic>cis</italic>-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 <italic>EGLN2</italic> expression in the European sample and two mQTLs were respectively detected in CpG sites in <italic>NRXN1</italic> and <italic>CYP2A7</italic>. Interestingly, we found for the first time that the minor allele of the single nucleotide polymorphism (SNP) rs3745277 located in <italic>CYP2A7P1</italic> (downstream of <italic>CYP2B6</italic>) significantly decreased methylation at the CpG site for <italic>CYP2A7</italic> (cg25427638; <italic>P</italic> = 5.31 × 10<sup>–7</sup>), reduced expression of <italic>CYP2B6</italic> (<italic>P</italic> = 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; <italic>P</italic> = 4.47 × 10<sup>–3</sup>) 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.</p>