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Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry

  • Vos, T. et al. Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA 328, 1604–1615 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Soriano, J. B., Murthy, S., Marshall, J. C., Relan, P. & Diaz, J. V. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect. Dis. 22, e102–e107 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 21, 133–146 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seeble, J. et al. Persistent symptoms in adult patients 1 year after coronavirus disease 2019 (COVID-19): a prospective cohort study. Clin. Infect. Dis. 74, 1191–1198 (2022).

    Article 

    Google Scholar
     

  • Tran, V. T., Porcher, R., Pane, I. & Ravaud, P. Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort. Nat. Commun. 13, 1812 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, X. et al. Genome-wide cross-trait analysis and Mendelian randomization reveal a shared genetic etiology and causality between COVID-19 and venous thromboembolism. Commun. Biol. 6, 441 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Taquet, M. et al. Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization. Nat. Med. 29, 2498–2508 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cervia-Hasler, C. et al. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science 383, eadg7942 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Davies, M. Long covid patients travel abroad for expensive and experimental ‘blood washing’. BMJ 378, o1671 (2022).

  • Uffelmann, E. et al. Genome-wide association studies. Nat. Rev. Methods Primers 1, 59 (2021).

    Article 

    Google Scholar
     

  • Davies, N. M., Holmes, M. V. & Davey Smith, G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362, k601 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sanderson, E. et al. Mendelian randomization. Nat. Rev. Methods Primers 2, 6 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658–665 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ardissino, M. et al. Birth weight influences cardiac structure, function, and disease risk: evidence of a causal association. Eur. Heart J. 45, 443−454 (2023).

  • Gaziano, L. et al. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nat. Med. 27, 668–676 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bovijn, J., Lindgren, C. M. & Holmes, M. V. Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19. Lancet Rheumatol. 2, e658–e659 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Niemi, M. E. K. et al. Mapping the human genetic architecture of COVID-19. Nature 600, 472–477 (2021).

    Article 

    Google Scholar
     

  • REMAP-CAP Investigators et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N. Engl. J. Med. 384, 1491–1502 (2021).

  • WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA 326, 499–518 (2021).

    Article 

    Google Scholar
     

  • Trajanoska, K. et al. From target discovery to clinical drug development with human genetics. Nature 620, 737–745 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Pierce, B. L. & Burgess, S. Efficient design for mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am. J. Epidemiol. 178, 1177–1184 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leinonen, J. T., Pirinen, M. & Tukiainen, T. Disentangling the link between maternal influences on birth weight and disease risk in 36,211 genotyped mother–child pairs. Commun. Biol. 7, 175 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Access results. FinnGen. https://www.finngen.fi/en/access_results.

  • Lammi, V. et al. Genome-wide association study of long COVID. Nat Genet. 57, 1402–1417 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burgess, S. & Thompson, S. G. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur. J. Epidemiol. 32, 377 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hemani, G., Tilling, K. & Davey Smith, G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 13, e1007081 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klarin, D. et al. Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease. Nat. Genet. 51, 1574–1579 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Evans, R. A. et al. Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study. Lancet Respir. Med. 9, 1275–1287 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Elneima, O. et al. Cohort profile: post-hospitalisation COVID-19 (PHOSP-COVID) study. Int. J. Epidemiol. 53, 165 (2024).

    Article 

    Google Scholar
     

  • Bilaloglu, S. et al. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA 324, 799–801 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Katsoularis, I. et al. Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. BMJ 377, e069590 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Kanai, M. et al. A second update on mapping the human genetic architecture of COVID-19. Nature 621, E7–E26 (2023).

    Article 

    Google Scholar
     

  • Angiolillo, D. J., Capodanno, D. & Goto, S. Platelet thrombin receptor antagonism and atherothrombosis. Eur. Heart J. 31, 17–28 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Smith, S. M. G. et al. PAR-1 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy. Platelets 16, 340–345 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Dupont, A. et al. An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN. Blood 101, 1833–1840 (2003).

    Article 
    PubMed 

    Google Scholar
     

  • Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329–338 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Woolf, B. et al. A drug target for erectile dysfunction to help improve fertility, sexual activity, and wellbeing: mendelian randomisation study. BMJ 383, e076197 (2023).

  • Zuber, V. et al. Combining evidence from Mendelian randomization and colocalization: review and comparison of approaches. Am. J. Hum. Genet. 109, 767–782 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aguet, F. et al. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    Article 

    Google Scholar
     

  • Kammers, K. et al. Transcriptional profile of platelets and iPSC-derived megakaryocytes from whole-genome and RNA sequencing. Blood 137, 959–968 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kahn, M. L., Hammes, S. R., Botka, C. & Coughlin, S. R. Gene and locus structure and chromosomal localization of the protease-activated receptor gene family. J. Biol. Chem. 273, 23290–23296 (1998).

    Article 
    PubMed 

    Google Scholar
     

  • Pretorius, E. et al. Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc. Diabetol. 20, 172 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mishra, A. et al. Stroke genetics informs drug discovery and risk prediction across ancestries. Nature 611, 115–123 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tcheandjieu, C. et al. Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. Nat. Med. 28, 1679–1692 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stevens, H., Canovas, R., Tran, H., Peter, K. & McFadyen, J. D. Inherited thrombophilias are associated with a higher risk of COVID-19–associated venous thromboembolism: a prospective population-based cohort study. Circulation 145, 940–942 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N. Engl. J. Med. 385, 790–802 (2021).

  • Spyropoulos, A. C. et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern. Med. 181, 1612–1620 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ryu, J. K. et al. Fibrin drives thromboinflammation and neuropathology in COVID-19. Nature 633, 905–913 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Swank, Z. et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin. Infect. Dis. 76, e487–e490 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Coughlin, S. R. Thrombin signalling and protease-activated receptors. Nature 407, 258–264 (2000).

    Article 
    PubMed 

    Google Scholar
     

  • Ludeman, M. J., Zheng, Y. W., Ishii, K. & Coughlin, S. R. Regulated shedding of PAR1 N-terminal exodomain from endothelial cells. J. Biol. Chem. 279, 18592–18599 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Riewald, M., Petrovan, R. J., Donner, A., Mueller, B. M. & Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296, 1880–1882 (2002).

    Article 
    PubMed 

    Google Scholar
     

  • Patel, Y. M. et al. A novel mutation in the P2Y12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. J. Thromb. Haemost. 12, 716–725 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Niessen, F. et al. Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation. Nature 452, 654–658 (2008).

    Article 
    PubMed 

    Google Scholar
     

  • Subramaniam, S. et al. A thrombin-PAR1/2 feedback loop amplifies thromboinflammatory endothelial responses to the viral RNA analogue poly(I:C). Blood Adv. 5, 2760–2774 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morrow, D. A. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404–1413 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Tricoci, P. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N. Engl. J. Med. 366, 20–33 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Khullar, D. et al. Racial/ethnic disparities in post-acute sequelae of SARS-CoV-2 infection in New York: an EHR-based cohort study from the RECOVER program. J. Gen. Intern. Med. 38, 1127–1136 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burgess, S., Davies, N. M. & Thompson, S. G. Bias due to participant overlap in two-sample Mendelian randomization. Genet. Epidemiol. 40, 597–608 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • FinnGen Public Documentation. https://finngen.gitbook.io/documentation/r10.

  • The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article 

    Google Scholar
     

  • Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wald, A. The fitting of straight lines if both variables are subject to error. Ann. Math. Stat. 11, 284–300 (1940).

    Article 

    Google Scholar
     

  • Hemani, G. et al. The MR-base platform supports systematic causal inference across the human phenome. eLife 7, e34408 (2018).

  • Yavorska, O. O. & Burgess, S. MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. Int. J. Epidemiol. 46, 1734–1739 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bowden, J., Davey Smith, G., Haycock, P. C. & Burgess, S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304–314 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hartwig, F. P., Smith, G. D. & Bowden, J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int. J. Epidemiol. 46, 1985–1998 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schuermans, A. et al. Genetic associations of circulating cardiovascular proteins with gestational hypertension and preeclampsia. JAMA Cardiol.9, 209−220 (2024).

  • Schuermans, A. et al. Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction. Nat. Cardiovasc. Res.3,1516−1530 (2024).

  • Henry, A. et al. Therapeutic targets for heart failure identified using proteomics and Mendelian randomization. Circulation 145, 1205–1217 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mahmoud, O., Dudbridge, F., Davey Smith, G., Munafo, M. & Tilling, K. A robust method for collider bias correction in conditional genome-wide association studies. Nat. Commun. 13, 619 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gaziano, J. M. et al. Million Veteran Program: a mega-biobank to study genetic influences on health and disease. J. Clin. Epidemiol. 70, 214–223 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Kanehisa, M. Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28, 27–30 (2000).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aguet, F. et al. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020).

    Article 

    Google Scholar
     

  • Becker, D. M. et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. JAMA 295, 1420–1427 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590, 290–299 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

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