UCLA

The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) virus. COVID-19 has been associated with multiorgan dysfunctions, including pulmonary, cardiovascular, metabolic, neurological, and psychiatric disorders, some of which can last weeks or months after viral contagion. Individual genome-wide association study (GWAS) studies have revealed specific genetic risk loci for COVID-19 severity. However, the small sample sizes and limited replication of studies prevents a comprehensive understanding of the mechanisms underlying COVID-19 severity and complications. Here we integrated the summary statistics from European and Chinese GWAS with tissue-specific expression quantitative loci (eQTLs) from GTEx and molecular pathways using Mergeomics to identify the tissue-specific molecular networks and key drivers of COVID-19 severity. We focused on tissues relevant to COVID complications, such as the lung, heart, blood, brain, intestine, and skin. Across the datasets, we discovered replicated pathways involved in viral transcription and activity, protein processing, and cell cycle and cancer, and predicted regulatory genes such as RARRES3, MIF-AS1, CXCL3, RNASE3, LY86, LCP2, SLC11A1, PSMB8, GBP4, ISG15, UQCRC2, and NCKAP1L and those for the major histocompatibility complex (MHC) Class I and II molecules. These pathways have downstream effects related to pulmonary, cardiovascular, autoimmune, skin dysfunctions, and some types of cancer. Identifying the pathways and regulatory genes will guide the discovery of therapeutic and pharmacological treatments for severe COVID-19 and subsequent complications.