Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

Emily Jamieson; Roxanna Korologou-Linden; Robyn E. Wootton; Anna L. Guyatt; Thomas Battram; Kimberley Burrows; Tom R. Gaunt; Martin D. Tobin; Marcus Munafò; George Davey Smith; Kate Tilling; Caroline Relton; Tom G. Richardson; Rebecca C. Richmond

doi:10.1016/j.ajhg.2020.01.015

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

Emily Jamieson, Roxanna Korologou-Linden, Robyn E. Wootton, Anna L. Guyatt, Thomas Battram, Kimberley Burrows, Tom R. Gaunt, Martin D. Tobin, Marcus Munafò, George Davey Smith, Kate Tilling, Caroline Relton, Tom G. Richardson, Rebecca C. Richmond^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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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 language	English
Pages (from-to)	315-326
Number of pages	12
Journal	American Journal of Human Genetics
Volume	106
Issue number	3
Early online date	20 Feb 2020
DOIs	https://doi.org/10.1016/j.ajhg.2020.01.015
Publication status	Published - 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

Research Groups and Themes

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

Keywords

smoking
lung function
DNA methylation
Mendelian randomization
mediation
causal inference

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2020.01.015

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Jamieson, E., Korologou-Linden, R., Wootton, R. E., Guyatt, A. L., Battram, T., Burrows, K., Gaunt, T. R., Tobin, M. D., Munafò, M., Davey Smith, G., Tilling, K., Relton, C., Richardson, T. G., & Richmond, R. C. (2020). Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways. American Journal of Human Genetics, 106(3), 315-326. https://doi.org/10.1016/j.ajhg.2020.01.015

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title = "Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways",

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.",

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author = "Emily Jamieson and Roxanna Korologou-Linden and Wootton, {Robyn E.} and Guyatt, {Anna L.} and Thomas Battram and Kimberley Burrows and Gaunt, {Tom R.} and Tobin, {Martin D.} and Marcus Munaf{\`o} and {Davey Smith}, George and Kate Tilling and Caroline Relton and Richardson, {Tom G.} and Richmond, {Rebecca C.}",

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: {\textcopyright} 2020 The Authors",

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doi = "10.1016/j.ajhg.2020.01.015",

language = "English",

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Jamieson, E, Korologou-Linden, R , Wootton, RE, Guyatt, AL, Battram, T, Burrows, K , Gaunt, TR, Tobin, MD, Munafò, M , Davey Smith, G , Tilling, K, Relton, C, Richardson, TG & Richmond, RC 2020, 'Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways', American Journal of Human Genetics, vol. 106, no. 3, pp. 315-326. https://doi.org/10.1016/j.ajhg.2020.01.015

TY - JOUR

T1 - Smoking, DNA Methylation, and Lung Function

T2 - a Mendelian Randomization Analysis to Investigate Causal Pathways

AU - Jamieson, Emily

AU - Korologou-Linden, Roxanna

AU - Wootton, Robyn E.

AU - Guyatt, Anna L.

AU - Battram, Thomas

AU - Burrows, Kimberley

AU - Gaunt, Tom R.

AU - Tobin, Martin D.

AU - Munafò, Marcus

AU - Davey Smith, George

AU - Tilling, Kate

AU - Relton, Caroline

AU - Richardson, Tom G.

AU - Richmond, Rebecca C.

N1 - 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

PY - 2020/3/5

Y1 - 2020/3/5

N2 - 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.

AB - 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.

KW - smoking

KW - lung function

KW - DNA methylation

KW - Mendelian randomization

KW - mediation

KW - causal inference

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U2 - 10.1016/j.ajhg.2020.01.015

DO - 10.1016/j.ajhg.2020.01.015

M3 - Article (Academic Journal)

C2 - 32084330

AN - SCOPUS:85080128081

SN - 0002-9297

VL - 106

SP - 315

EP - 326

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

Abstract

Bibliographical note

Research Groups and Themes

Keywords

UN SDGs

Access to Document

Handle.net

Other files and links

Embargoed Document

Fingerprint

IEU 2 Relton Programme - Epigenetic Epidemiology

Rework of IEU 2 Tilling Programme

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

Abstract

Bibliographical note

Research Groups and Themes

Keywords

UN SDGs

Access to Document

Handle.net

Other files and links

Embargoed Document

Fingerprint

Projects

IEU 2 Relton Programme - Epigenetic Epidemiology

Rework of IEU 2 Tilling Programme

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this