Fig. 3. Epigenetic changes in CpGs associated with environmental respiratory traits differentiate COVID19 progression and mild cases from autoimmune disorders.

a Hierarchical clustering of methylation DMCs for both discovery and replication cohorts (Ward’s hierarchical agglomerative clustering with Pearson correlation as distance is used). Individual methylation values are averaged by severity from severe cases (top), mild cases (middle) to negative lab tested SARS-CoV2 (bottom). The annotations in the upper part of the plot refer to the analysis to which each CpG is differentially methylated (black). Four CpG modules highly replicated between cohorts, were selected from the hierarchical clustering: S.Ho (blue, hypomethylated with the severity), S.He (red, hypermethylated with the severity) and M.He (yellow, hypermethylated in mild compared with severe patients and healthy controls). b Reactome significant pathways by CpG module (two-tailed hypergeometric p-value < 0.01) are shown. c MethBank EWAS trait enrichment by CpG module (two-tailed hypergeometric p-value < 1e-10) are shown. d Significant overrepresentation of transcription factor binding site prediction (HOMER, two-tailed hypergeometric p-value < 0.001) is depicted by CpG module. e Average log2FC Pearson correlations between COVID19 severity groups and seven different systemic autoimmune conditions (SLE Systemic lupus erythematosus, RA Rheumatoid arthritis, pSjS Primary Sjögren’s syndrome, SSc Systemic sclerosis, MCTD Mixed connective tissue disease, PAPs Primary antiphospholipid syndrome, UCTD Undifferentiated connective tissue disease). DMCs are grouped by CpG modules.