Abstract
Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV1. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization (“moloc”) framework. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p < 1.2 × 10−4). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites might influence lung function via effects on smoking. By using “moloc”, we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.
Highlights
Cigarette smoking is a major risk factor for lung disease, which is often preceded by a rapid decline in lung function.[1]
For the smoking-related CpG sites that could be proxied by mQTLs, we looked up the identified mQTLs in the lung function genome-wide association study (GWAS) summary data from the UK Biobank
DNA Methylation and Lung Function: Direction of Causality Where there was evidence that DNA methylation might have a causal effect on lung function, we evaluated the possibility of reverse causation, whereby a SNP used as a proxy for DNA methylation has its primary effect through lung function rather than through DNA methylation
Summary
Cigarette smoking is a major risk factor for lung disease, which is often preceded by a rapid decline in lung function.[1]. Smoking is associated with substantial changes to methylation levels at many loci across the genome.[3] For example, hypomethylation at the CpG site cg05575921 in intron 3 of the aryl hydrocarbon receptor repressor (AHRR) gene is strongly associated with both the current and past smoking behavior of an individual,[3,4] and it has recently been suggested to mediate a proportion of the effect of smoking on decreased lung function.[5] it is not clear that this association represents a true causal pathway.[6] DNA methylation at other CpG sites related to lung function might serve as a potential mediator on the pathway from smoking.[7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
