Document Type
Article
Publication Date
8-17-2022
Publication Title
Cell systems
Keywords
JGM, COVID-19, GWAS, Mendelian randomization, NK cell, gene discovery, genome-wide association study, machine learning, network analysis, rare variant analysis, single-cell multiomic profiling
JAX Source
Cell Syst . 2022 Aug 17;13(8):598-614.e6.
Volume
13
Issue
8
First Page
598
Last Page
614000000
PMID
35690068
DOI
10.1016/j.cels.2022.05.007
Grant
We acknowledge the Stanford Genetics Bioinformatics Service Center (GBSC) for providing computational infrastructure for this study. This study was sup- ported by the National Institutes of Health (1S10OD023452-01 to GBSC; CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442 to M.P.S.) and the Wellcome Trust (216596/Z/19/Z to J.C.-K.). Figure 1 was created with BioRender.com. We thank the COVID-19 Host Genetics Initiative (https:// www.covid19hg.org/) for releasing the summary statistics data of GWAS and rare variant association study. We also thank GenOMICC (https://genomicc. org/) for sharing the GWAS summary statistics data to us.
Abstract
The determinants of severe COVID-19 in healthy adults are poorly understood, which limits the opportunity for early intervention. We present a multiomic analysis using machine learning to characterize the genomic basis of COVID-19 severity. We use single-cell multiome profiling of human lungs to link genetic signals to cell-type-specific functions. We discover >1,000 risk genes across 19 cell types, which account for 77% of the SNP-based heritability for severe disease. Genetic risk is particularly focused within natural killer (NK) cells and T cells, placing the dysfunction of these cells upstream of severe disease. Mendelian randomization and single-cell profiling of human NK cells support the role of NK cells and further localize genetic risk to CD56 NK cells, which are key cytokine producers during the innate immune response. Rare variant analysis confirms the enrichment of severe-disease-associated genetic variation within NK-cell risk genes. Our study provides insights into the pathogenesis of severe COVID-19 with potential therapeutic targets.
Recommended Citation
Zhang S,
Cooper-Knock J,
Weimer AK,
Shi M,
Kozhaya L,
Unutmaz D,
Harvey C,
Julian TH,
Furini S,
Frullanti E,
Fava F,
Renieri A,
Gao P,
Shen X,
Timpanaro IS,
Kenna KP,
Baillie JK,
Davis MM,
Tsao PS,
Snyder MP.
Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity Cell Syst . 2022 Aug 17;13(8):598-614.e6.
Comments
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).