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Meta-analysis identifies 3,207 novel DNA methylation sites linked to smoking

Meta-analysis identifies 3,207 novel DNA methylation sites linked to smoking
Photo by Rick Rothenberg / Unsplash
Key Takeaway
Interpret these 3,207 novel smoking-methylation associations as observational findings requiring replication before clinical use.

This meta-analysis examined DNA methylation patterns associated with smoking exposure in 45,460 participants from the Million Veteran Program, including 27,455 Europeans, 11,798 African Americans, and 4,859 Admixed Americans. The study compared ever smokers to never smokers and identified 3,207 novel probe-smoking associations, adding to the known epigenetic effects of tobacco exposure.

The analysis leveraged a large, ancestrally diverse sample to uncover methylation sites not previously reported. However, effect sizes, confidence intervals, and p-values were not reported, limiting the ability to assess the strength of these associations. The study did not report follow-up duration or adjust for potential confounders beyond smoking status.

As a meta-analysis of observational data, these findings cannot establish causality. The authors did not discuss limitations or practice implications. The results highlight the need for further validation in independent cohorts and exploration of functional relevance.

Clinically, these epigenetic markers may eventually serve as biomarkers of smoking exposure or risk, but current evidence is preliminary. No specific interventions or clinical recommendations can be drawn from this study alone.

Study Details

Study typeMeta analysis
EvidenceLevel 1
PublishedApr 2026
View Original Abstract ↓
The Million Veteran Program (MVP) represents the largest and one of the most diverse single cohorts associated with longitudinal Electronic Health Record data (EHR) data. We profiled a subset of samples from MVP using the Illumina Infinium MethylationEPIC Beadchip (EPIC array) to generate one of the largest single cohort methylation dataset to-date. Methylation profiles were analyzed for 45,460 total individuals, with the most populous ancestries composed of 27,455 Europeans, 11,798 African Americans, and 4,859 Admixed Americans. We detail the strict quality control standards implemented to ensure the most robust method of methylation profiling of the MVP cohort. This dataset was then applied to evaluate the effects of smoking exposure on DNA methylation in MVP participants. Ancestry-stratified epigenome-wide association studies (EWAS) of smoking status (ever/never) were performed using over 750,000 probes with certifiable signal. Our multi-ancestry meta-analysis demonstrates replicability with existing EWAS and identifies 3,207 novel probe-smoking associations unlocked via the depth and breadth of data in this cohort.
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