Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study
Abstract Background Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation. Methods The methylati...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Clinical Epigenetics |
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| Online Access: | http://link.springer.com/article/10.1186/s13148-018-0452-9 |
| _version_ | 1818421043631489024 |
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| author | Shuai Li Ee Ming Wong Minh Bui Tuong L. Nguyen Ji-Hoon Eric Joo Jennifer Stone Gillian S. Dite Graham G. Giles Richard Saffery Melissa C. Southey John L. Hopper |
| author_facet | Shuai Li Ee Ming Wong Minh Bui Tuong L. Nguyen Ji-Hoon Eric Joo Jennifer Stone Gillian S. Dite Graham G. Giles Richard Saffery Melissa C. Southey John L. Hopper |
| author_sort | Shuai Li |
| collection | DOAJ |
| description | Abstract Background Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation. Methods The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin pairs, and 215 sisters of twins from 130 twin families using the Infinium HumanMethylation450K BeadChip array. Linear regression was used to estimate associations between methylation at ~ 410,000 cytosine-guanine dinucleotides (CpGs) and smoking status. A regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess putative causation. Results At a 5% false discovery rate, 39 CpGs located at 27 loci, including previously reported AHRR, F2RL3, 2q37.1 and 6p21.33, were found to be differentially methylated across never, former and current smokers. For all 39 CpG sites, current smokers had the lowest methylation level. Our study provides the first replication for two previously reported CpG sites, cg06226150 (SLC2A4RG) and cg21733098 (12q24.32). From the ICE FALCON analysis with smoking status as the predictor and methylation score as the outcome, a woman’s methylation score was associated with her co-twin’s smoking status, and the association attenuated towards the null conditioning on her own smoking status, consistent with smoking status causing changes in methylation. To the contrary, using methylation score as the predictor and smoking status as the outcome, a woman’s smoking status was not associated with her co-twin’s methylation score, consistent with changes in methylation not causing smoking status. Conclusions For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with smoking. Our study suggests that smoking has a causal effect on peripheral blood DNA methylation, but not vice versa. |
| first_indexed | 2024-12-14T13:04:05Z |
| format | Article |
| id | doaj.art-fc6cfbea24d44420936b1edd5cc319b7 |
| institution | Directory Open Access Journal |
| issn | 1868-7075 1868-7083 |
| language | English |
| last_indexed | 2024-12-14T13:04:05Z |
| publishDate | 2018-02-01 |
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| series | Clinical Epigenetics |
| spelling | doaj.art-fc6cfbea24d44420936b1edd5cc319b72022-12-21T23:00:22ZengBMCClinical Epigenetics1868-70751868-70832018-02-0110111210.1186/s13148-018-0452-9Causal effect of smoking on DNA methylation in peripheral blood: a twin and family studyShuai Li0Ee Ming Wong1Minh Bui2Tuong L. Nguyen3Ji-Hoon Eric Joo4Jennifer Stone5Gillian S. Dite6Graham G. Giles7Richard Saffery8Melissa C. Southey9John L. Hopper10Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneGenetic Epidemiology Laboratory, Department of Pathology, University of MelbourneCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneGenetic Epidemiology Laboratory, Department of Pathology, University of MelbourneCentre for Genetic Origins of Health and Disease, Curtin University and the University of Western AustraliaCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneMurdoch Children’s Research Institute, Royal Children’s HospitalGenetic Epidemiology Laboratory, Department of Pathology, University of MelbourneCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneAbstract Background Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation. Methods The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin pairs, and 215 sisters of twins from 130 twin families using the Infinium HumanMethylation450K BeadChip array. Linear regression was used to estimate associations between methylation at ~ 410,000 cytosine-guanine dinucleotides (CpGs) and smoking status. A regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess putative causation. Results At a 5% false discovery rate, 39 CpGs located at 27 loci, including previously reported AHRR, F2RL3, 2q37.1 and 6p21.33, were found to be differentially methylated across never, former and current smokers. For all 39 CpG sites, current smokers had the lowest methylation level. Our study provides the first replication for two previously reported CpG sites, cg06226150 (SLC2A4RG) and cg21733098 (12q24.32). From the ICE FALCON analysis with smoking status as the predictor and methylation score as the outcome, a woman’s methylation score was associated with her co-twin’s smoking status, and the association attenuated towards the null conditioning on her own smoking status, consistent with smoking status causing changes in methylation. To the contrary, using methylation score as the predictor and smoking status as the outcome, a woman’s smoking status was not associated with her co-twin’s methylation score, consistent with changes in methylation not causing smoking status. Conclusions For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with smoking. Our study suggests that smoking has a causal effect on peripheral blood DNA methylation, but not vice versa.http://link.springer.com/article/10.1186/s13148-018-0452-9DNA methylationSmokingEpigenome-wide association studyCausal inferenceFamily study |
| spellingShingle | Shuai Li Ee Ming Wong Minh Bui Tuong L. Nguyen Ji-Hoon Eric Joo Jennifer Stone Gillian S. Dite Graham G. Giles Richard Saffery Melissa C. Southey John L. Hopper Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study Clinical Epigenetics DNA methylation Smoking Epigenome-wide association study Causal inference Family study |
| title | Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study |
| title_full | Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study |
| title_fullStr | Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study |
| title_full_unstemmed | Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study |
| title_short | Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study |
| title_sort | causal effect of smoking on dna methylation in peripheral blood a twin and family study |
| topic | DNA methylation Smoking Epigenome-wide association study Causal inference Family study |
| url | http://link.springer.com/article/10.1186/s13148-018-0452-9 |
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