Longitudinal study of genome-wide DNA methylation in individuals with and without post-acute symptoms following SARS-CoV-2 infection

<h4>Background</h4>Symptoms following SARS-CoV-2 infection, referred to as Long-COVID, have been reported since the pandemic. We investigated whether COVID-19 or Long-COVID is associated with persistent genome-wide DNA methylation (DNAm) changes in whole blood using a longitudinal design.<h4>Methods</h4>DNAm was measured using the Illumina EPIC V2 platform (859,651 CpGs) in 297 adult participants (594 samples in total) from two Norwegian population-based cohorts, with samples collected pre-infection (2020) and during the pandemic (2023). Participants were classified as Long-COVID, COVID-19 (no persistent symptoms), or not infected.<h4>Results</h4>No significant DNAm differences were observed between Long-COVID and not infected at either time point (<i>p</i> = 0.745(FDR)) or during the pandemic specifically (<i>p</i> = 0.629(FDR)). Likewise, no differences were detected between COVID-19 and not infected across both time points (<i>p</i> = 0.883(FDR)) or during the pandemic (<i>p</i> = 0.287(FDR)). Sex-stratified analyses of the X chromosome revealed no significant DNAm differences for Long-COVID or COVID-19 in males (both <i>p</i> = 0.999(FDR)) or females (both <i>p</i> = 0.999(FDR)). Epigenetic age acceleration was also evaluated using DunedinPACE (DP) and PhenoAge (PA), but no significant differences were detected for Long-COVID (<i>p</i> = 0.695 [DP], <i>p</i> = 0.528 [PA]) or COVID-19 (<i>p</i> = 0.624 [DP], <i>p</i> = 0.348 [PA]).<h4>Conclusion</h4>No persistent epigenetic age- or DNAm based differences due to Long-COVID or SARS-CoV-2 infection were detected in our cohorts.