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We applied Mendelian randomization including &gt;3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support\/death due to COVID-19 (ORs = 1.12\u20131.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support\/death (ORs = 0.80\u20130.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86\u20130.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support\/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support\/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010042","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T13:54:24Z","timestamp":1646315664000},"page":"e1010042","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":37,"title":["Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5748-6652","authenticated-orcid":true,"given":"Alish B.","family":"Palmos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1919-9649","authenticated-orcid":true,"given":"Vincent","family":"Millischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3228-9692","authenticated-orcid":true,"given":"David K.","family":"Menon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2350-2332","authenticated-orcid":true,"given":"Timothy R.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie S.","family":"Taams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8693-8926","authenticated-orcid":true,"given":"Benedict","family":"Michael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9040-5949","authenticated-orcid":true,"given":"Geraint","family":"Sunderland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Griffiths","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"COVID Clinical Neuroscience Study Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"H\u00fcbel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerome","family":"Breen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"pgen.1010042.ref001","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19","volume":"181","author":"D Blanco-Melo","year":"2020","journal-title":"Cell"},{"key":"pgen.1010042.ref002","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.3389\/fimmu.2020.01441","article-title":"Immune Response, Inflammation, and the Clinical Spectrum of COVID-19.","volume":"11","author":"LF Garc\u00eda","year":"2020","journal-title":"Front Immunol"},{"key":"pgen.1010042.ref003","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An interactive web-based dashboard to track COVID-19 in real time","volume":"20","author":"E Dong","year":"2020","journal-title":"Lancet Infect Dis"},{"key":"pgen.1010042.ref004","doi-asserted-by":"crossref","first-page":"m1985","DOI":"10.1136\/bmj.m1985","article-title":"Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study","volume":"369","author":"AB Docherty","year":"2020","journal-title":"BMJ"},{"key":"pgen.1010042.ref005","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1056\/NEJMcp2009575","article-title":"Severe Covid-19.","volume":"383","author":"DA Berlin","year":"2020","journal-title":"N Engl J Med"},{"key":"pgen.1010042.ref006","doi-asserted-by":"crossref","DOI":"10.1128\/mSphere.00344-20","article-title":"COVID-19: an Immunopathological View","volume":"5","author":"K. 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