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To identify genetic variants influencing COVID\u201019 severity progression, whole\u2010exome sequencing was performed, followed by an exome\u2010wide association study on 191 hospitalized patients categorized into three severity groups. The analysis identified nine loci surpassing the suggestive significance threshold (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20093\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ): rs2180196 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20092.09,\n                    <jats:italic>TGM1\u2010RABGGTA<\/jats:italic>\n                    ), rs2236232 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u2009\u22121.37,\n                    <jats:italic>PLEKHH1<\/jats:italic>\n                    ), rs7886938 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20091.66,\n                    <jats:italic>FMO6P<\/jats:italic>\n                    ), rs2929047 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u2009\u22121.16,\n                    <jats:italic>XKR4<\/jats:italic>\n                    ), rs9841237 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20091.21,\n                    <jats:italic>SI<\/jats:italic>\n                    ), rs34357454 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20091.92,\n                    <jats:italic>NID2<\/jats:italic>\n                    ), rs1005887 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20091.28,\n                    <jats:italic>DUSP18<\/jats:italic>\n                    ), rs2281880 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u2009\u22121.11,\n                    <jats:italic>SUFU<\/jats:italic>\n                    ), and rs73061693 (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20091.66,\n                    <jats:italic>TULP2<\/jats:italic>\n                    ). Furthermore, binomial exact test identified 218 SNPs in COVID\u201019\u2010related genes with significant allele frequency differences between severity groups, including 61 novel variants. Of those 218, co\u2010occurring SNP pairs were identified within specific severity groups, including pairs in\n                    <jats:italic>JAK1\u2010PIK3R2<\/jats:italic>\n                    in critical patients and eight pairs in genes\n                    <jats:italic>IL6<\/jats:italic>\n                    ,\n                    <jats:italic>SERPINE1<\/jats:italic>\n                    ,\n                    <jats:italic>COL5A1, MAPK14, FREM1, C7, GLS, ATP5PO<\/jats:italic>\n                    , and\n                    <jats:italic>RPL7<\/jats:italic>\n                    in severe patients. Clinical data analysis confirmed known risk factors like older age in men and specific comorbidities and revealed distinct therapeutic and biochemical profiles across severity groups. This study confirms known genetic risks and reveals novel variants, providing a more detailed basis for understanding COVID\u201019 pathogenesis and for developing genetic diagnostic and prognostic biomarkers.\n                  <\/jats:p>","DOI":"10.1002\/jmv.70984","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T05:52:41Z","timestamp":1779861161000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Layered Genomic and Clinical Analysis Identifies Novel Variants, Co\u2010Occurring Single Nucleotide Polymorphism Pairs, and Clinical Determinants of Host\u2010Pathogen Interaction in COVID\u201019 Severity"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1116-4986","authenticated-orcid":false,"given":"Doris","family":"Repu\u0161i\u0107","sequence":"first","affiliation":[{"name":"Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science University of Zagreb  Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4892-0204","authenticated-orcid":false,"given":"Marina","family":"Korolija","sequence":"additional","affiliation":[{"name":"Dubrava University Hospital Zagreb Croatia"},{"name":"Forensic Science Centre Ivan Vu\u010deti\u0107 Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-1677","authenticated-orcid":false,"given":"Ana","family":"Livun","sequence":"additional","affiliation":[{"name":"Dubrava University Hospital Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-1239","authenticated-orcid":false,"given":"Tomo","family":"Svagu\u0161a","sequence":"additional","affiliation":[{"name":"Dubrava University Hospital Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1780-9928","authenticated-orcid":false,"given":"Robert","family":"Belu\u017ei\u0107","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Ru\u0111er Bo\u0161kovi\u0107 Institute  Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5237-2215","authenticated-orcid":false,"given":"Vjekoslav","family":"Tomai\u0107","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Ru\u0111er Bo\u0161kovi\u0107 Institute  Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1291-2897","authenticated-orcid":false,"given":"Rosa","family":"Karli\u0107","sequence":"additional","affiliation":[{"name":"Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science University of Zagreb  Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5705-2464","authenticated-orcid":false,"given":"Kristian","family":"Vlahovi\u010dek","sequence":"additional","affiliation":[{"name":"Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science University of Zagreb  Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"e_1_2_12_3_1","unstructured":"World Health Organization World Health Organization COVID\u201019 Dashboard accessed December 13 2024 https:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/MEDICINA58020144"},{"key":"e_1_2_12_5_1","article-title":"Guidelines for the Treatment of Patients With Coronavirus Disease 2019 (COVID\u201019)","author":"Puljiz I.","year":"2022","journal-title":"Ministry of Health of the Republic of Croatia"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0250602"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-023-06034-3"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103629"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41431-020-0636-6"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/S12916-020-01673-Z\/FIGURES\/2"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.622176"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/FGENE.2023.1240245\/FULL"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0105090"},{"key":"e_1_2_12_14_1","unstructured":"R Core Team \"R: A Language and Environment for Statistical Computing \" R Foundation for Statistical Computing 2023."},{"key":"e_1_2_12_15_1","unstructured":"B.Bushnell \"BBMap: A Fast. 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