{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:39:39Z","timestamp":1768563579453,"version":"3.49.0"},"posted":{"date-parts":[[2023,5,28]]},"group-title":"Genetic and Genomic Medicine","reference-count":40,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Early evidence that patients with (multiple) pre-existing diseases are at highest risk for severe COVID-19 has been instrumental in the pandemic to allocate critical care resources and later vaccination schemes. However, systematic studies exploring the breadth of medical diagnoses, including common, but non-fatal diseases are scarce, but may help to understand severe COVID-19 among patients at supposedly low risk. Here, we systematically harmonized &gt;12 million primary care and hospitalisation health records from \u223c500,000 UK Biobank participants into 1448 collated disease terms to systematically identify diseases predisposing to severe COVID-19 (requiring hospitalisation or death) and its post-acute sequalae, Long COVID. We identified a total of 679 diseases associated with an increased risk for severe COVID-19 (n=672) and\/or Long COVID (n=72) that spanned almost all clinical specialties and were strongly enriched in clusters of cardio-respiratory and endocrine-renal diseases. For 57 diseases, we established consistent evidence to predispose to severe COVID-19 based on survival and genetic susceptibility analyses. This included a possible role of symptoms of malaise and fatigue as a so far largely overlooked risk factor for severe COVID-19. We finally observed partially opposing risk estimates at known risk loci for severe COVID-19 for etiologically related diseases, such as post-inflammatory pulmonary fibrosis (e.g.,\n                  <jats:italic>MUC5B<\/jats:italic>\n                  ,\n                  <jats:italic>NPNT<\/jats:italic>\n                  , and\n                  <jats:italic>PSMD3<\/jats:italic>\n                  ) or rheumatoid arthritis (e.g.,\n                  <jats:italic>TYK2<\/jats:italic>\n                  ), possibly indicating a segregation of disease mechanisms. Our results provide a unique reference that demonstrates how 1) complex co-occurrence of multiple \u2013 including non-fatal \u2013 conditions predispose to increased COVID-19 severity and 2) how incorporating the whole breadth of medical diagnosis can guide the interpretation of genetic risk loci.\n                <\/jats:p>","DOI":"10.1101\/2023.05.23.23290408","type":"posted-content","created":{"date-parts":[[2023,5,29]],"date-time":"2023-05-29T00:20:17Z","timestamp":1685319617000},"source":"Crossref","is-referenced-by-count":1,"title":["Complex patterns of multimorbidity associated with severe COVID-19 and Long COVID"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3437-9963","authenticated-orcid":false,"given":"Maik","family":"Pietzner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9612-7791","authenticated-orcid":false,"given":"Spiros","family":"Denaxas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Summaira","family":"Yasmeen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria A.","family":"Ulmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9510-5646","authenticated-orcid":false,"given":"Tomoko","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4666-0923","authenticated-orcid":false,"given":"Matthias","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2368-7322","authenticated-orcid":false,"given":"Gabi","family":"Kastenm\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2279-0624","authenticated-orcid":false,"given":"Harry","family":"Hemingway","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Langenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024070310300802000_2023.05.23.23290408v3.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm8108"},{"key":"2024070310300802000_2023.05.23.23290408v3.2","unstructured":"GOV.uk. No Title. https:\/\/www.gov.uk\/government\/news\/clinically-extremely-vulnerable-receive-updated-guidance-in-line-with-new-national-restrictions."},{"key":"2024070310300802000_2023.05.23.23290408v3.3","doi-asserted-by":"publisher","DOI":"10.5888\/pcd18.210123"},{"key":"2024070310300802000_2023.05.23.23290408v3.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0247461"},{"key":"2024070310300802000_2023.05.23.23290408v3.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2521-4"},{"key":"2024070310300802000_2023.05.23.23290408v3.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003501"},{"key":"2024070310300802000_2023.05.23.23290408v3.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06034-3"},{"key":"2024070310300802000_2023.05.23.23290408v3.8","doi-asserted-by":"crossref","first-page":"E7","DOI":"10.1038\/s41586-023-06355-3","article-title":"A second update on mapping the human genetic architecture of COVID-19","volume":"621","author":"COVID-19 Host Genetics Initiative","year":"2023","journal-title":"Nature"},{"key":"2024070310300802000_2023.05.23.23290408v3.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175508"},{"key":"2024070310300802000_2023.05.23.23290408v3.10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-biodatasci-122320-112352","article-title":"Using Phecodes for Research with the Electronic Health Record: From PheWAS to PheRS","volume":"4","year":"2021","journal-title":"Annu. 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