@article{9d1e5e6429b24ea19be84a95ee63fb74,
title = "Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity",
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 CD56bright 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.",
keywords = "COVID-19, GWAS, Mendelian randomization, NK cell, gene discovery, genome-wide association study, machine learning, network analysis, rare variant analysis, single-cell multiomic profiling",
author = "Sai Zhang and Johnathan Cooper-Knock and Weimer, {Annika K} and Minyi Shi and Lina Kozhaya and Derya Unutmaz and Calum Harvey and Julian, {Thomas H} and Simone Furini and Elisa Frullanti and Francesca Fava and Alessandra Renieri and Peng Gao and Xiaotao Shen and Timpanaro, {Ilia Sarah} and Kenna, {Kevin P} and Baillie, {J Kenneth} and Davis, {Mark M} and Tsao, {Philip S} and Snyder, {Michael P}",
note = "Funding Information: We acknowledge the Stanford Genetics Bioinformatics Service Center (GBSC) for providing computational infrastructure for this study. This study was supported 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. S.Z. J.C.-K. P.S.T. and M.P.S. conceived and designed the study. S.Z. J.C.-K. A.K.W. M.S. L.K. D.U. C.H. T.H.J. J.K.B. P.S.T. and M.P.S. were responsible for data acquisition. S.Z. J.C.-K. C.H. T.H.J. and J.K.B. were responsible for data analysis. S.Z. J.C.-K. A.K.W. C.H. T.H.J. S.F. E.F. F.F. A.R. P.G. X.S. I.S.T. K.P.K. J.K.B. M.M.D. P.S.T. and M.P.S. were responsible for the interpretation of the findings. S.Z. J.C.-K. P.S.T. and M.P.S. drafted the manuscript with assistance from all authors. All authors meet the four ICMJE authorship criteria and were responsible for revising the manuscript, approving the final version for publication, and for accuracy and integrity of the work. M.P.S. is a co-founder and member of the scientific advisory board of Personalis, Qbio, January, SensOmics, Protos, Mirvie, NiMo, Onza, and Oralome. He is also on the scientific advisory board of Danaher, Genapsys, and Jupiter. No other authors have competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = aug,
day = "17",
doi = "10.1016/j.cels.2022.05.007",
language = "English",
volume = "13",
pages = "598--614.e6",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "8",
}