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. 2022 Oct 10;41(1):140–149. doi: 10.1038/s41587-022-01475-z

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — a, HuRI interactors (gray nodes) of COVID-19 ‘critical illness proteins’ loci (seed, red nodes) include a significant (P = 0.0009, empirical test) number of direct SARS-CoV-2 targeted proteins (purple nodes). A total of 144 additional seed protein interactors are not resolved individually. Node and edge colors according to legend. b, Genes in indicated COVID-19 datasets ranked across the human genome by number of publications. Number of publications is indicated by the top panel on log scale. Asterisks indicate significant differences relative to COVID-19-associated genes^32,33; NS, P = 1 (HuSCI) and P = 0.36 (Stuckalov et al.); *P = 0.047; ****P = 0.000014, two-sided Mann–Whitney U test, Bonferroni correction, from top to bottom: n = 45, 170, 383, 876 and 849; error bars are 95% confidence intervals of the mean, calculated by 1,000 bootstrap samples. c, Virus-interactor enrichment: number of direct SARS-CoV-2 protein interacting HuSCI proteins in the subnetwork formed by proteins encoded by seed proteins^32,33 and their first-level interactors (arrow) compared to n = 10,000 randomized control networks (gray distribution). d, Of 3,603 communities in Human Reference Interactome (HuRI) with ≥4 members (step 1), 204 are significantly targeted by SARS-CoV-2 (two-sided nominal P < 0.05; Fisher’s exact test) (step 2); Gene Ontology (GO) enrichment identifies functions associated with each community (step 3); and MAGMA identifies 31 communities significantly associated with human traits (FDR < 0.05) (step 4), the great majority of which are COVID-19 comorbidities. Example community 28 is significantly targeted by SARS-CoV-2 in HuSCI (two-sided P = 0.0078; Fisher’s exact test, uncorrected) and enriched for negative regulation of adaptive immune response and viral transcription. Functional descriptors in squared boxes according to legend (Supplementary Table 8); relation of indicated traits to COVID-19 is indicated in rightmost column as general link (+) (e.g., via immunity) and clinical evidence for modulation of diseases symptoms and risk for severe or long COVID ( + + ; Extended Data Fig. 3f). BMI, body mass index.