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 one second (FEV1) in UK Biobank (n=321,047) using two-sample Mendelian randomization (MR), with replication in the SpiroMeta consortium (n=79,055). Secondly, we investigated whether DNA methylation mediates the effect of smoking on FEV1 using two-step MR. Lastly, we evaluated the presence of horizontal pleiotropy and also assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression, using a multiple-trait colocalization framework. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p<1.2x10-4). Replication analysis supported a causal effect at three CpGs (cg21201401 (LIME1/ZGPAT), cg19758448 (PGAP3) and cg12616487 (EML3/AHNAK) (p<0.0028)). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites may influence lung function via effects on smoking. Using multiple-trait colocalization, we found evidence of shared causal variants between lung function, gene expression and DNA methylation. Findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.
Original languageEnglish
Pages (from-to)315-326
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number3
Early online date20 Feb 2020
Publication statusE-pub ahead of print - 20 Feb 2020

Structured keywords

  • ICEP
  • Bristol Population Health Science Institute
  • Tobacco and Alcohol
  • Physical and Mental Health


  • smoking
  • lung function
  • DNA methylation
  • Mendelian randomization
  • mediation
  • causal inference

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