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

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(1)) in UK Biobank (n = 321,047) by using two-sample Mendelian randomizati...

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Autores principales: Jamieson, Emily, Korologou-Linden, Roxanna, Wootton, Robyn E., Guyatt, Anna L., Battram, Thomas, Burrows, Kimberley, Gaunt, Tom R., Tobin, Martin D., Munafò, Marcus, Davey Smith, George, Tilling, Kate, Relton, Caroline, Richardson, Tom G., Richmond, Rebecca C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058834/
https://www.ncbi.nlm.nih.gov/pubmed/32084330
http://dx.doi.org/10.1016/j.ajhg.2020.01.015
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author Jamieson, Emily
Korologou-Linden, Roxanna
Wootton, Robyn E.
Guyatt, Anna L.
Battram, Thomas
Burrows, Kimberley
Gaunt, Tom R.
Tobin, Martin D.
Munafò, Marcus
Davey Smith, George
Tilling, Kate
Relton, Caroline
Richardson, Tom G.
Richmond, Rebecca C.
author_facet Jamieson, Emily
Korologou-Linden, Roxanna
Wootton, Robyn E.
Guyatt, Anna L.
Battram, Thomas
Burrows, Kimberley
Gaunt, Tom R.
Tobin, Martin D.
Munafò, Marcus
Davey Smith, George
Tilling, Kate
Relton, Caroline
Richardson, Tom G.
Richmond, Rebecca C.
author_sort Jamieson, Emily
collection PubMed
description 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(1)) 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(1). 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(1) 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 FEV(1), 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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spelling pubmed-70588342020-09-05 Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways Jamieson, Emily Korologou-Linden, Roxanna Wootton, Robyn E. Guyatt, Anna L. Battram, Thomas Burrows, Kimberley Gaunt, Tom R. Tobin, Martin D. Munafò, Marcus Davey Smith, George Tilling, Kate Relton, Caroline Richardson, Tom G. Richmond, Rebecca C. Am J Hum Genet Article 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(1)) 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(1). 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(1) 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 FEV(1), 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. Elsevier 2020-03-05 2020-02-20 /pmc/articles/PMC7058834/ /pubmed/32084330 http://dx.doi.org/10.1016/j.ajhg.2020.01.015 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jamieson, Emily
Korologou-Linden, Roxanna
Wootton, Robyn E.
Guyatt, Anna L.
Battram, Thomas
Burrows, Kimberley
Gaunt, Tom R.
Tobin, Martin D.
Munafò, Marcus
Davey Smith, George
Tilling, Kate
Relton, Caroline
Richardson, Tom G.
Richmond, Rebecca C.
Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways
title Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways
title_full Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways
title_fullStr Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways
title_full_unstemmed Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways
title_short Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways
title_sort smoking, dna methylation, and lung function: a mendelian randomization analysis to investigate causal pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058834/
https://www.ncbi.nlm.nih.gov/pubmed/32084330
http://dx.doi.org/10.1016/j.ajhg.2020.01.015
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