Multi-omics analyses of the complex interplay between genetic variants, DNA methylation, and gene expression in COVID-19.

Publication date: Jul 01, 2025

Background: SARS-CoV-2, which drove the 2019 COVID-19 pandemic, continues to engender inquiries into the role of host genetic factors in disease susceptibility. Despite the identification of over 1,000 genes potentially associated with SARS-CoV-2 and COVID-19, the mechanisms connecting genetic variants to phenotype remain elusive. To shed light on these mechanisms, we undertook an integrated analysis, merging data from whole-genome association analyses of COVID-19 with methylome and transcriptomic. Methods: Study includes African American adults from the GENE-FORECAST study, encompassing 371 individuals with whole genome sequencing (WGS), 203 with DNA methylation, and 321 with RNA sequencing (RNA-Seq) of blood. 53. 3% of participants reported COVID-19. Significant loci associated with COVID-19 were examined within the framework of methylation quantitative trait loci (mQTL) which located near the gene-of-original (cis-mQTL) and expression quantitative trait loci (eQTL) which located near the gene-of-origin (cis-eQTL), enabling analysis to assess mediators between genetic variants and COVID-19 status. Results: Our analysis identified four intronic variants and confirmed a missense variant, rs1052067, in PMF1 associated with COVID-19. Causal mediation analysis revealed that the combination of genetic variants within PMF1, epigenomics, and transcriptomics mapped four pathways influencing COVID-19 status. These pathways include: rs9659072 -> DNAm at chr1:156285845 (annotated to TMEM79) -> ENSG00000198715:13 (annotated to GLMP); rs12083543 -> DNAm at chr1:155951748 (ARHGEF2) -> ENSG00000198715:13 (GLMP); rs1052067 -> DNAm at chr1:155951748 (ARHGEF2)-> ENSG00000198715:13 (GLMP); rs1543294 -> ENSG00000198715:13 (GLMP) -> DNAm at chr1:156077518 (MEX3A). Conclusions: Through integrated multi-omics analyses, we identified genetic variants whose effects on COVID-19 susceptibility are mediated by changes in DNA methylation and mRNA expression. These findings offer insights into potential mechanistic pathways that merit further exploration.

Semantics

Original Article