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Yao, C.* ; Joehanes, R.* ; Wilson, R. ; Tanaka, T.* ; Ferrucci, L.* ; Kretschmer, A. ; Prokisch, H. ; Schramm, K. ; Gieger, C. ; Peters, A. ; Waldenberger, M. ; Marzi, C. ; Herder, C.* ; Levy, D.*

Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases.

Clin. Epigenet. 13:60 (2021)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. RESULTS: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. CONCLUSIONS: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Chrna5 ; Copd ; Ewas ; Lung Cancer ; Mendelian Randomization ; Smoking
ISSN (print) / ISBN 1868-7075
e-ISSN 1868-7083
Zeitschrift Clinical Epigenetics
Quellenangaben Band: 13, Heft: 1, Seiten: , Artikelnummer: 60 Supplement: ,
Verlag Springer
Verlagsort Berlin : Heidelberg
Begutachtungsstatus Peer reviewed
Förderungen German Federal Ministry of Education and Research (Berlin, Germany)
Ministry of Culture and Science of the state North Rhine-Westphalia (Dusseldorf, Germany)
German Diabetes Center - German Federal Ministry of Health (Berlin, Germany)
Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
State of Bavaria
Helmholtz Zentrum Munchen -German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
National Institutes of Health (NIH)