Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer and coronary disease pathways.

Identification of the plasma proteomic changes of Coronavirus disease 2019 (COVID-19) is essential to understanding the pathophysiology of the disease and developing predictive models and novel therapeutics. We performed plasma deep proteomic profiling from 332 COVID-19 patients and 150 controls and pursued replication in an independent cohort (297 cases and 76 controls) to find potential biomarkers and causal proteins for three COVID-19 outcomes (infection, ventilation, and death). We identified and replicated 1,449 proteins associated with any of the three outcomes (841 for infection, 833 for ventilation, and 253 for death) that can be query on a web portal ( https://covid.proteomics.wustl.edu/ ). Using those proteins and machine learning approached we created and validated specific prediction models for ventilation (AUC>0.91), death (AUC>0.95) and either outcome (AUC>0.80). These proteins were also enriched in specific biological processes, including immune and cytokine signaling (FDR ≤ 3.72×10 ), Alzheimer's disease (FDR ≤ 5.46×10 ) and coronary artery disease (FDR ≤ 4.64×10 ). Mendelian randomization using pQTL as instrumental variants nominated BCAT2 and GOLM1 as a causal proteins for COVID-19. Causal gene network analyses identified 141 highly connected key proteins, of which 35 have known drug targets with FDA-approved compounds. Our findings provide distinctive prognostic biomarkers for two severe COVID-19 outcomes (ventilation and death), reveal their relationship to Alzheimer's disease and coronary artery disease, and identify potential therapeutic targets for COVID-19 outcomes.