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.

中文翻译：

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吸烟、DNA 甲基化和肺功能：用于研究因果途径的孟德尔随机分析。


吸烟相关的 DNA 甲基化是否对肺功能有因果影响尚未得到彻底评估。我们首先使用两个样本孟德尔随机化 (MR) 研究了英国生物银行 (n = 321,047) 中 474 个与吸烟相关的 CpG 对 1 秒用力呼气量 (FEV1) 的因果影响，然后在 SpiroMeta 联盟中重复了这项研究（ n = 79,055)。其次，我们使用两步 MR 来研究 DNA 甲基化是否介导吸烟对 FEV1 的影响。最后，我们评估了水平多效性的存在，并通过使用多性状共定位（“moloc”）框架评估了是否有任何证据表明肺功能、DNA 甲基化和基因表达之间存在共同的因果遗传变异。我们发现了 DNA 甲基化可能对 18 CpG 处的 FEV1 产生因果影响的证据 (p < 1.2 × 10-4)。复制分析支持三个 CpG（cg21201401 [LIME1 和 ZGPAT]、cg19758448 [PGAP3] 和 cg12616487 [EML3 和 AHNAK] [p < 0.0028]）的因果效应。尽管某些位点的 DNA 甲基化可能通过吸烟影响肺功能，但 DNA 甲基化并未明显介导吸烟对 FEV1 的影响。通过使用“moloc”，我们发现了肺功能、基因表达和 DNA 甲基化之间共有因果变异的证据。这些发现强调了改善肺功能和可能戒烟的潜在治疗目标，尽管需要更大的组织特异性数据集来证实这些结果。