Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which drove the 2019 coronavirus disease (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. The 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. About 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 are located near the gene-of-orig (-mQTL) and expression quantitative trait loci (eQTL), which are located near the gene-of-origin (-eQTL), enabling analysis to assess mediators between genetic variants and COVID-19 status. Our analysis identified four intronic variants and confirmed a missense variant, rs1052067, inassociated with COVID-19. Causal mediation analysis revealed that the combination of genetic variants within, epigenomics, and transcriptomics mapped four pathways influencing COVID-19 status. These pathways include: rs9659072→DNAm at chr1:156285845 (annotated to)→ENSG00000198715:13 (annotated to glycosylated lysosomal membrane protein,); rs12083543→DNAm at chr1:155951748 ()→ENSG00000198715:13 (); rs1052067→DNAm at chr1:155951748 ()→ENSG00000198715:13 (); rs1543294→ENSG00000198715:13 ()→DNAm at chr1:156077518 (). Through integrated multiomics 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.The study investigates host genetic factors influencing COVID-19 susceptibility by integrating WGS, epigenomics, and transcriptomic data. It identified that PMF1 is linked to COVID-19. Mediation analysis revealed that genetic variants in PMF1 affect COVID-19 status via combinations of one transcript (annotated to GLMP) and three DNAm sites (annotated to ARHGEF2, TMEM79, MEX3A). The findings highlight the role of lysosomal pathways and transmembrane proteins in disease susceptibility, offering new insight into potential therapeutic targets for COVID-19. cis cis PMF1PMF1TMEM79GLMP ARHGEF2GLMP ARHGEF2GLMP GLMP MEX3A NEW & NOTEWORTHY
