Medical Research Council Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Psychological Science, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK; National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol National Health Service Foundation Trust and University of Bristol, Bristol, UK.
Am J Hum Genet. 2020 Mar 5;106(3):315-326. doi: 10.1016/j.ajhg.2020.01.015. Epub 2020 Feb 20.
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 (FEV) 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 FEV. 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 FEV at 18 CpGs (p < 1.2 × 10). 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 FEV, 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.
吸烟相关的 DNA 甲基化是否对肺功能有因果影响尚未得到充分评估。我们首先通过两样本 Mendelian 随机化（MR）方法在 UK Biobank 中（n = 321,047）研究了 474 个与吸烟相关的 CpG 对 1 秒用力呼气量（FEV）的因果影响，然后在 SpiroMeta 联盟中（n = 79,055）对其进行了重复研究。其次，我们使用两步 MR 方法来研究 DNA 甲基化是否介导了吸烟对 FEV 的影响。最后，我们使用多性状 colocalization（“moloc”）框架来评估是否存在水平多效性，并评估肺功能、DNA 甲基化和基因表达之间是否存在共同的因果遗传变异。我们在 18 个 CpG 位点（p < 1.2 × 10）发现了 DNA 甲基化对 FEV 可能存在因果关系的证据。复制分析支持三个 CpG 位点（cg21201401 [LIME1 和 ZGPAT]、cg19758448 [PGAP3] 和 cg12616487 [EML3 和 AHNAK]）（p < 0.0028）存在因果关系。尽管某些位点的 DNA 甲基化可能通过对吸烟的影响来影响肺功能，但 DNA 甲基化并没有明确介导吸烟对 FEV 的影响。通过使用“moloc”，我们发现了肺功能、基因表达和 DNA 甲基化之间存在共同因果变异的证据。这些发现强调了改善肺功能和可能戒烟的潜在治疗靶点，但需要更大、更具组织特异性的数据集来证实这些结果。
