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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.

Original languageEnglish
Pages (from-to)315-326
Number of pages12
JournalAmerican Journal of Human Genetics
Volume106
Issue number3
Early online date20 Feb 2020
DOIs
Publication statusPublished - 5 Mar 2020

Bibliographical note

Funding Information:
We thank the SpiroMeta Consortium for contributing summary statistics to this work. We would also like to thank Alice Carter, Dipender Gill, and Eleanor Sanderson for useful discussions regarding the mediation analysis. This study was made possible with the financial support of Jonathan de Pass and Georgina de Pass. This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/4, MC_UU_00011/5, and MC_UU_00011/7). This work was also supported by CRUK (grant number C18281/A19169 ) and the ESRC (grant number ES/N000498/1 ). T.B. and R.K.L. are supported by Wellcome Trust PhD studentships (203746 and 215193/Z18/Z). T.G.R. is a UKRI Innovation Research Fellow (MR/S003886/1). R.C.R. is a de Pass Vice Chancellor Research Fellow at the University of Bristol. A.L.G. is funded by internal fellowships at the University of Leicester for the Wellcome Trust Institutional Strategic Support Fund (WT204801/Z/16/Z) and the BHF Accelorator Award (AA/18/3/34220). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The research was partially supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the NIHR Leicester Biomedical Research Centre: the views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Funding Information:
We thank the SpiroMeta Consortium for contributing summary statistics to this work. We would also like to thank Alice Carter, Dipender Gill, and Eleanor Sanderson for useful discussions regarding the mediation analysis. This study was made possible with the financial support of Jonathan de Pass and Georgina de Pass. This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/4, MC_UU_00011/5, and MC_UU_00011/7). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). T.B. and R.K.L. are supported by Wellcome Trust PhD studentships (203746 and 215193/Z18/Z). T.G.R. is a UKRI Innovation Research Fellow (MR/S003886/1). R.C.R. is a de Pass Vice Chancellor Research Fellow at the University of Bristol. A.L.G. is funded by internal fellowships at the University of Leicester for the Wellcome Trust Institutional Strategic Support Fund (WT204801/Z/16/Z) and the BHF Accelorator Award (AA/18/3/34220). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The research was partially supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the NIHR Leicester Biomedical Research Centre: the views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Funding Information:
M.D.T. has received grant support from GSK and Orion Pharma. All other authors declare no competing interests.

Publisher Copyright:
© 2020 The Authors

Structured keywords

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

Keywords

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

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