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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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13148-021-01041-5.

clinical epigenetics

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