BACKGROUND: Evidence for persistent epigenetic changes in individuals who had a mild SARS-CoV-2 infection is limited, as most DNA methylation (DNAm) studies to date have focused on either the acute phase of infection or on the months following infection in severe cases requiring hospitalization.
METHODS AND RESULTS: Using the Infinium Human MethylationEPIC BeadChip, we investigated blood DNA methylation (DNAm) up to four months after SARS-CoV-2 infection in cases and controls from four population-based cohorts (NAKO, Lifelines, CON-VINCE, and TiKoCo; n = 675) within the framework of the ORCHESTRA Consortium. We observed DNAm changes at 16 differentially methylated positions (DMPs) and 21 differentially methylated regions (DMRs), with 89% of these DMPs/DMRs hypomethylated in cases compared to age- and sex-matched controls. Genes mapped to these CpGs were annotated with Gene Ontology terms and pathways related to immune responses to viral infection. eQTM analyses in whole blood from an independent cohort (KORA FF4 study) produced 49 significant CpG-transcript pairs, including IFI44L and GNA12. Despite inter-individual variability and cohort heterogeneity, our findings regarding four DMPs (IFI44L, MX1, DDX60, and RABGAP1L) and two DMRs (PARP9 and GNA12) replicate changes described both in the acute phase of infection and at long-term follow-up. Differential methylation at other novel loci may reflect the systemic nature of post-infection epigenetic changes.
CONCLUSION: Our findings suggest moderate but persistent epigenetic changes up to four months after SARS-CoV-2 infection in mild cases from population-based cohorts. These changes partially mirror those reported during the acute phase of both mild and severe COVID-19 and overlap with pathways dysregulated in autoimmune, metabolic and neurological disease. Future research should examine epigenetic changes associated with persisting symptoms in long COVID, investigate downstream effects of DNAm changes on other -omics, and consider longer follow-up periods to further elucidate the molecular mechanisms underlying SARS-CoV-2 induced epigenetic changes.
