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

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.
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.
No significant DNAm differences were observed between Long-COVID and not infected at either time point (p = 0.745(FDR)) or during the pandemic specifically (p = 0.629(FDR)). Likewise, no differences were detected between COVID-19 and not infected across both time points (p = 0.883(FDR)) or during the pandemic (p = 0.287(FDR)). Sex-stratified analyses of the X chromosome revealed no significant DNAm differences for Long-COVID or COVID-19 in males (both p = 0.999(FDR)) or females (both p = 0.999(FDR)). Epigenetic age acceleration was also evaluated using DunedinPACE (DP) and PhenoAge (PA), but no significant differences were detected for Long-COVID (p = 0.695 [DP], p = 0.528 [PA]) or COVID-19 (p = 0.624 [DP], p = 0.348 [PA]).
No persistent epigenetic age- or DNAm based differences due to Long-COVID or SARS-CoV-2 infection were detected in our cohorts.
Some people continue to experience symptoms for months after a COVID-19 infection. If symptoms persist for more than three months, the condition is often diagnosed as Long-COVID. Scientists are still trying to understand why some people develop long-lasting symptoms while others recover fully. One possible explanation is that COVID-19 might cause lasting changes in how genes are regulated in the body. In this study, we looked at a biological process called DNA methylation that helps control how genes are turned on or off. Changes in this process can sometimes reflect long-term effects of illness or aging. We analyzed blood samples from 297 adults in Norway. Each person gave a sample before the COVID-19 pandemic and another sample during the pandemic resulting in 594 samples in total. We compared people who had Long-COVID, people who had COVID-19 but recovered without long-term symptoms, and people who did not report being infected. We did not find any persistent clear differences in DNA methylation both within- or between these groups. We also looked at measures of biological aging based on DNA methylation patterns but found no differences related to COVID-19 or Long-COVID. Hence, we did not detect long-term changes in DNA methylation in blood that could be attributed to COVID-19 and Long-COVID in our cohorts. Larger studies, employing higher resolution DNA methylation methodology, may be needed to determine whether smaller or more specific changes occur.