GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, 2023, Pairo-Castineira, Ponting, Baillie et al

Abstract

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3.

Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data.

We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Open access, https://www.nature.com/articles/s41586-023-06034-3

 

Why is COVID life-threatening for some people? Genetics study offers clues

"Baillie and his colleagues analysed data from more than 24,000 people and combined this information with data sets from around the world. They found 49 DNA sequences that are associated with becoming critically ill from COVID-19. Sixteen of these had not been reported previously.

Among these sequences are some that could affect the activity of genes and proteins involved in the immune system. Raging immune cells have long been implicated in causing some of the tissue damage seen in late-stage, severe cases of COVID-19. Baillie and his colleagues found genetic links to inflammatory responses and the activation of immune cells — processes that can damage the lungs and reduce their capacity to send oxygen to the body’s tissues.

“It definitely expands our understanding of the genetic determinants of severe COVID,” says Brent Richards, a human geneticist at McGill University in Montreal, Canada. Richards is an investigator on another project called the COVID-19 Host Genetics Initiative, a global effort in which scientists from more than 54 countries share data."

https://www.nature.com/articles/d41586-023-01655-0

 

This might correlate with last year's findings in Long Covid: Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome (2022) —

 

See also Generation of potentially inhibitory autoantibodies to ADAMTS13 in coronavirus disease (2023)