GWAS and meta-analysis identifies multiple new genetic mechanisms underlying severe Covid-19

Abstract

Pulmonary inflammation drives critical illness in Covid-19, creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C and SCOURGE studies, and meta-analysis with previously-reported data. We find an additional \numconvincingnew new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.

ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19

“…Apart from the (refined) annotation of causal genes at known risk loci, establishing a shared signal across different molecular layers and COVID-19 subthreshold findings can reveal yet-to-be-identified risk genes and proteins. For example, we identified RAB2A, encoding Rasrelated protein Rab2A, as a suggestive causal gene for severe COVID-19, which has only been identified as a genome-wide significant locus while this paper was under review with substantially larger case numbers 82 . While other findings, including CSF3 (encoding G-CSF), still warrant statistical identification at genome-wide significance for COVID-19 outcomes before being unambiguously declared as genetic risk locus, we argue that establishing convergence of different biological entities at a genetic signal can greatly increase confidence in the plausibility of findings.…”

Comorbidities, multimorbidity and COVID-19

“…In COVID-19, recent work has suggested that variants that affect the key viral-entry mechanisms for SARS-CoV-2 in human cells (ACE2 and TMPRSS2 proteins) alter the probability of the mutant causing severe disease 41 . However, ACE2 is also involved in blood pressure homeostasis, and ACE inhibitors, used as a first-line approach to managing hypertension, are associated with increased ACE2 expression in some organs 42 .…”

Colocalization of expression transcripts with COVID-19 outcomes is rare across cell states, cell types and organs

“…The immune response is mediated by different immune cell subtypes, including CD4 + T cells, acting at varying time points during infection across tissues (Ong et al 2020 ; Tan et al 2021 ). Understanding the dynamics of this process may pinpoint targets helpful for COVID-19 interventions, as previously shown (De Biasi et al 2020 ; Degenhardt et al 2022 ; Kundu et al 2022 ; Mathew et al 2020 ; Pairo-Castineira et al 2022 ; Severe Covid et al 2020 ; Wang et al 2022 ; Zhou et al 2021 ).…”