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Novel genes and sex differences in COVID-19 severity.

ABSTRACT: Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

SUBMITTER: Cruz R

PROVIDER: S-EPMC9652109 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Novel genes and sex differences in COVID-19 severity.

Cruz Raquel R Diz-de Almeida Silvia S López de Heredia Miguel M Quintela Inés I Ceballos Francisco C FC Pita Guillermo G Lorenzo-Salazar José M JM González-Montelongo Rafaela R Gago-Domínguez Manuela M Sevilla Porras Marta M Tenorio Castaño Jair Antonio JA Nevado Julian J Aguado Jose María JM Aguilar Carlos C Aguilera-Albesa Sergio S Almadana Virginia V Almoguera Berta B Alvarez Nuria N Andreu-Bernabeu Álvaro Á Arana-Arri Eunate E Arango Celso C Arranz María J MJ Artiga Maria-Jesus MJ Baptista-Rosas Raúl C RC Barreda-Sánchez María M Belhassen-Garcia Moncef M Bezerra Joao F JF Bezerra Marcos A C MAC Boix-Palop Lucía L Brion María M Brugada Ramón R Bustos Matilde M Calderón Enrique J EJ Carbonell Cristina C Castano Luis L Castelao Jose E JE Conde-Vicente Rosa R Cordero-Lorenzana M Lourdes ML Cortes-Sanchez Jose L JL Corton Marta M Darnaude M Teresa MT De Martino-Rodríguez Alba A Del Campo-Pérez Victor V Diaz de Bustamante Aranzazu A Domínguez-Garrido Elena E Luchessi Andre D AD Eiros Rocío R Estigarribia Sanabria Gladys Mercedes GM Carmen Fariñas María M Fernández-Robelo Uxía U Fernández-Rodríguez Amanda A Fernández-Villa Tania T Gil-Fournier Belén B Gómez-Arrue Javier J González Álvarez Beatriz B Gonzalez Bernaldo de Quirós Fernan F González-Peñas Javier J Gutiérrez-Bautista Juan F JF Herrero María José MJ Herrero-Gonzalez Antonio A Jimenez-Sousa María A MA Lattig María Claudia MC Liger Borja Anabel A Lopez-Rodriguez Rosario R Mancebo Esther E Martín-López Caridad C Martín Vicente V Martinez-Nieto Oscar O Martinez-Lopez Iciar I Martinez-Resendez Michel F MF Martinez-Perez Angel A Mazzeu Juliana F JF Merayo Macías Eleuterio E Minguez Pablo P Moreno Cuerda Victor V Silbiger Vivian N VN Oliveira Silviene F SF Ortega-Paino Eva E Parellada Mara M Paz-Artal Estela E Santos Ney P C NPC Pérez-Matute Patricia P Perez Patricia P Pérez-Tomás M Elena ME Perucho Teresa T Pinsach-Abuin Mel Lina ML Pompa-Mera Ericka N EN Porras-Hurtado Gloria L GL Pujol Aurora A Ramiro León Soraya S Resino Salvador S Fernandes Marianne R MR Rodríguez-Ruiz Emilio E Rodriguez-Artalejo Fernando F Rodriguez-Garcia José A JA Ruiz Cabello Francisco F Ruiz-Hornillos Javier J Ryan Pablo P Soria José Manuel JM Souto Juan Carlos JC Tamayo Eduardo E Tamayo-Velasco Alvaro A Taracido-Fernandez Juan Carlos JC Teper Alejandro A Torres-Tobar Lilian L Urioste Miguel M Valencia-Ramos Juan J Yáñez Zuleima Z Zarate Ruth R Nakanishi Tomoko T Pigazzini Sara S Degenhardt Frauke F Butler-Laporte Guillaume G Maya-Miles Douglas D Bujanda Luis L Bouysran Youssef Y Palom Adriana A Ellinghaus David D Martínez-Bueno Manuel M Rolker Selina S Amitrano Sara S Roade Luisa L Fava Francesca F Spinner Christoph D CD Prati Daniele D Bernardo David D Garcia Federico F Darcis Gilles G Fernández-Cadenas Israel I Holter Jan Cato JC Banales Jesus M JM Frithiof Robert R Duga Stefano S Asselta Rosanna R Pereira Alexandre C AC Romero-Gómez Manuel M Nafría-Jiménez Beatriz B Hov Johannes R JR Migeotte Isabelle I Renieri Alessandra A Planas Anna M AM Ludwig Kerstin U KU Buti Maria M Rahmouni Souad S Alarcón-Riquelme Marta E ME Schulte Eva C EC Franke Andre A Karlsen Tom H TH Valenti Luca L Zeberg Hugo H Richards Brent B Ganna Andrea A Boada Mercè M de Rojas Itziar I Ruiz Agustín A Sánchez-Juan Pascual P Real Luis Miguel LM Guillen-Navarro Encarna E Ayuso Carmen C González-Neira Anna A Riancho José A JA Rojas-Martinez Augusto A Flores Carlos C Lapunzina Pablo P Carracedo Angel A

Human molecular genetics 20221101 22

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants ...[more]

PMID: 35708486

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Project description:Using RNA-seq and high-resolution mass spectrometry we performed a comprehensive systems analysis on 128 plasma and leukocyte samples from hospitalized patients with or without COVID-19 (n=102 and 26 respectively) and with differing degrees of disease severity. We generated abundance measurements for over 17,000 transcripts, proteins, metabolites, and lipids and compiled them with clinical data into a curated relational database. This resource offers the unique opportunity to perform systems analysis and cross-ome correlations to both molecules and patient outcomes. In total 219 molecular features were mapped with high significance to COVID-19 status and severity, including those involved in processes such as complement system activation, dysregulated lipid transport, and B cell activation. In one example, we detected a trio of covarying molecules – citrate, plasmenyl-phosphatidylcholines, and gelsolin (GSN) – that offer both pathophysiological insight and potential novel therapeutic targets. Further, our data revealed in some cases, and supported in others, that several biological processes were dysregulated in COVID-19 patients including vessel damage, platelet activation and degranulation, blood coagulation, and acute phase response. For example, we observed that the coagulation-related protein, cellular fibronectin (cFN), was highly increased within COVID-19 patients and provide new evidence that the upregulated proteoform stems from endothelial cells, consistent with endothelial injury as a major activator of the coagulation cascade. The abundance of prothrombin, which is cleaved to form thrombin during clotting, was significantly reduced and correlated with severity and might help to explain the hyper coagulative environment of SARS-CoV-2 infection. From transcriptomic analysis of leukocytes, we concluded that COVID-19 patients with acute respiratory distress syndrome (ARDS) demonstrated a phenotype that overlapped with, but was distinct from, that found in patients with non-COVID-19-ARDS. To aid in the global efforts toward elucidation of disease pathophysiology and therapeutic development, we created a web-based tool with interactive visualizations allowing for easy navigation of this systems-level compendium of biomolecule abundance in relation to COVID-19 status and severity. Finally, we leveraged these multi-omic data to predict COVID-19 patient outcomes with machine learning, which highlighted the predictive power of these expansive molecular measurements beyond the standardized clinical estimate of 10-year survival Charlson score.

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Novel genes and sex differences in COVID-19 severity.

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Novel genes and sex differences in COVID-19 severity.

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