# Epigenome-wide association study (EWAS)

An epigenome-wide association study (EWAS) is a hypothesis-free scan. It tests whether DNA methylation at hundreds of thousands of CpG sites (spots where a cytosine next to a guanine can gain a methyl tag) is linked to some trait. The trait could be your age, a disease, or an environmental exposure. Methylation is usually measured with microarrays (commonly Illumina's 450K or EPIC/850K chips) or whole-genome bisulfite sequencing. That gives a 'beta-value' from 0 to 1 for each site. Then a regression is run at every CpG, correcting for multiple testing and for confounders (like estimated blood-cell proportions). In aging research, EWAS produced many of the CpG sets behind the first epigenetic clocks. Hannum et al. (2013) used 656 blood samples, ages 19 to 101, to find 71 age-linked CpGs that predicted biological age accurately in other cohorts. Similar work led to Horvath's 353-CpG pan-tissue clock. The EWAS Catalog (Battram et al., 2022) gathers over 1.7 million associations from more than 2,600 studies, so you can look up CpG-trait links across cohorts. One persistent problem is reverse causation. A disease or aging process can itself reshape the methylome. So an association does not prove the CpG change comes first or drives the outcome. That is why Mendelian randomization and longitudinal designs are increasingly paired with EWAS to triangulate cause.

## Sources

- Hannum G, Guinney J, Zhao L, et al.. (2013). Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates. Molecular Cell. https://doi.org/10.1016/j.molcel.2012.10.016
- Battram T, Yousefi P, Crawford G, et al.. (2022). The EWAS Catalog: a database of epigenome-wide association studies. Wellcome Open Research. https://doi.org/10.12688/wellcomeopenres.17598.2
- Birney E, Davey Smith G, Greally JM. (2016). Epigenome-wide Association Studies and the Interpretation of Disease -Omics. PLOS Genetics. https://doi.org/10.1371/journal.pgen.1006105

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_Canonical: https://longevity-switzerland.com/en/glossary/ewas · Part of Longevity Cities · Updated 2026-06-22_