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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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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. |
format | Online Article Text |
id | pubmed-7058834 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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