Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19

Area of Science:

• Genomics
• Infectious Diseases
• Human Genetics

Background:

• The genetic underpinnings of COVID-19 (coronavirus disease 2019) susceptibility and severity remain incompletely understood.
• Identifying specific genes and biological pathways involved is crucial for understanding the disease and developing targeted interventions.

Purpose of the Study:

• To employ an integrative genomics approach to pinpoint candidate genes contributing to COVID-19 and its clinical outcomes.
• To investigate potential causal relationships between gene expression, plasma protein levels, and COVID-19 risk.

Main Methods:

• Combined gene expression quantitative trait loci (eQTLs) and plasma protein quantitative trait loci (pQTLs) with COVID-19 genome-wide association study (GWAS) data.
• Utilized Bayesian colocalization (COLOC) to assess shared genetic signals between eQTLs/pQTLs and COVID-19 GWAS loci.
• Applied summary-based and multi-variable two-sample Mendelian randomization (MR) to infer causal associations between genes, proteins, and COVID-19.

Main Results:

• Identified 18 genes whose expression in lung and/or blood co-localized with COVID-19 genetic loci.
• Confirmed previously reported associations for genes like LZTFL1, SLC6A20, and IFNAR2, and identified a causal link for OAS1.
• Demonstrated a significant causal association between plasma ABO protein levels and COVID-19 risk, with higher levels correlating to increased risk, especially for severe disease.

Conclusions:

• The study successfully identified and prioritized candidate genes implicated in COVID-19 pathogenesis through integrative genomics.
• Provides the first evidence of a causal relationship between plasma ABO protein levels and COVID-19, highlighting the role of blood type-related proteins.
• Findings offer valuable insights for future research into COVID-19 mechanisms and potential therapeutic targets.