Purpose SARS-CoV-2 causes a severe inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea and in ~5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping.

Methods We integrated genetic and blood DNA methylation information, analysed them together with clinical information in a sample of ~100 healthy controls and ~470 SARS-CoV-2 PCR tested patients recruited from two different clinical centers and compared with seven different systemic autoimmune diseases (SADs) from the PRECISESADS cohort.

Results The EWAS revealed widespread epigenetic variation associated with COVID-19 phenotypes, which were enriched in molecular pathways related with SADs and differed between mild and severe COVID19 cases. Among them, interferon, FCGR mediated phagocytosis and CD209 signatures in severe and mild COVID-19 were shared with seven different SADs (including systemic lupus erythematosus). Environmental trait-related CpG sites were found to be specifically hypermethylated in mild SARS-CoV-2 positive cases. These sites were enriched in key regulators of inflammatory cytokine gene expression known to be part of the cytokine storm described in the most severe outcomes of the disease. Additionally, these DNA methylation changes were found to be differentially regulated by genetic variants and associated with different regulatory mechanisms.

Conclusions The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. Our work reveals pathways involved in COVID19 pathogenesis both shared and not shared with SADs, novel risk variants with epigenetic downstream effects, and illustrate how the genetic architecture of DNA methylation depends on the infection status and severity of COVID19. In addition, the analyses suggest that an interaction between environment, genetics and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.