78442f9a0a1e2740dbecc443eeb0fd19 321335.pdf 84cb8813c47a86ee5712c92f5c5c0d84bd4fea37 321335.pdf b13a8239833b16ca41027ee6a33a1889cf3ded5f03dd61eda3e3e2ff117eb98d 321335.pdf Title: Global and Sex-Stratified Genome-Wide Association Study of Long COVID Based on Patient-Driven Symptom Recall Subject: We aimed to explore the global and sex-specific genetic variants associated with long COVID, as defined by patient-driven symptom recall. A 1-year cohort study of 2411 COVID-19 patients collected long COVID symptoms with an open-ended, non-directed questionnaire, and long COVID incidence was determined according to the World Health Organization definition. Global and sex-stratified genome-wide association analyses were conducted by logistic regression models adjusted for age, sex (in the global analysis), and the first 10 principal components. We assessed sex-variant interactions and performed gene-based analyses, gene mapping, and gene-set enrichment analyses. When comparing the 1392 long COVID cases with the non-cases, we identified 23 lead variants from suggestive signals: 13 from the global analysis, 5 from females, and 5 from males. Five variants showed a significant interaction with sex (two in females, three in males). We mapped 15 protein-coding genes related to diseases of the immune and nervous systems and tumoral processes. Notably, CD5 and VPS37C, linked to immune function, were significantly associated with long COVID in men. Our results suggest that persistent immune dysregulation may be involved in the development of precisely defined long COVID. Keywords: post-acute COVID-19 syndrome; COVID-19; SARS-CoV-2; genome-wide association study; genetic polymorphism; sex characteristics Author: Sara Polo-Alonso, Álvaro Hernáez, Irene R. Dégano, Ruth Martí-Lluch, Mel·lina Pinsach-Abuin, Roberto Elosua, Isaac Subirana, Marta Puigmulé, Alexandra Pérez, Raquel Cruz, Silvia Diz-de Almeida, Eulàlia Puigdecant, Elisabet Selga, Xavier Nogues, Joan Ramon Masclans, Roberto Güerri-Fernández, Héctor Cubero-Gallego, Helena Tizon-Marcos, Beatriz Vaquerizo, Ramon Brugada, Rafel Ramos, Anna Camps-Vilaró and Jaume Marrugat Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Tue Sep 23 11:11:24 2025 CEST ModDate: Tue Sep 23 11:21:02 2025 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1099725 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ASJIQB+CMBSY10 Type 1 Builtin yes yes yes 121 0 WNWTFR+VnURWPalladioL-Bold Type 1 Custom yes yes yes 122 0 DNBTZY+URWPalladioL-Bold Type 1 Custom yes yes yes 123 0 MVNGND+URWPalladioL-Roma Type 1 Custom yes yes yes 124 0 MEHHCT+VnURWPalladioL Type 1 Custom yes yes yes 125 0 SHFMYH+URWPalladioL-Ital Type 1 Custom yes yes yes 126 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes yes 204 0 SSJMKU+CMSY10 Type 1 Builtin yes yes yes 205 0 PFPAGA+PalatinoLinotype TrueType WinAnsi yes yes no 171 0 PFPAFO+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 172 0 PFPAGA+PalatinoLinotype TrueType WinAnsi yes yes no 197 0 CTGVMV+EURB7 Type 1 Builtin yes yes yes 245 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-02-14 04:22:27 CET RepresentationInformation: 321335.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-02-13 14:38:19 CET Size: 1099725 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 483 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Results Children: Item: Title: Participants Item: Title: Genome-Wide Association Analysis and Variant–Sex Interaction Item: Title: Functional Annotation Item: Title: Discussion Item: Title: Materials and Methods Children: Item: Title: Study Design and Participants Item: Title: Definition of Long COVID Item: Title: DNA Collection Item: Title: Genotyping Item: Title: Quality Control of Genotype Data Item: Title: Variant Imputation Item: Title: Clinical Data Item: Title: Statistical Analyses Item: Title: Functional Annotation Item: Title: Conclusions Item: Title: References Info: Title: Global and Sex-Stratified Genome-Wide Association Study of Long COVID Based on Patient-Driven Symptom Recall Author: Sara Polo-Alonso, Álvaro Hernáez, Irene R. Dégano, Ruth Martí-Lluch, Mel·lina Pinsach-Abuin, Roberto Elosua, Isaac Subirana, Marta Puigmulé, Alexandra Pérez, Raquel Cruz, Silvia Diz-de Almeida, Eulàlia Puigdecant, Elisabet Selga, Xavier Nogues, Joan Ramon Masclans, Roberto Güerri-Fernández, Héctor Cubero-Gallego, Helena Tizon-Marcos, Beatriz Vaquerizo, Ramon Brugada, Rafel Ramos, Anna Camps-Vilaró and Jaume Marrugat Subject: We aimed to explore the global and sex-specific genetic variants associated with long COVID, as defined by patient-driven symptom recall. A 1-year cohort study of 2411 COVID-19 patients collected long COVID symptoms with an open-ended, non-directed questionnaire, and long COVID incidence was determined according to the World Health Organization definition. Global and sex-stratified genome-wide association analyses were conducted by logistic regression models adjusted for age, sex (in the global analysis), and the first 10 principal components. We assessed sex-variant interactions and performed gene-based analyses, gene mapping, and gene-set enrichment analyses. When comparing the 1392 long COVID cases with the non-cases, we identified 23 lead variants from suggestive signals: 13 from the global analysis, 5 from females, and 5 from males. Five variants showed a significant interaction with sex (two in females, three in males). We mapped 15 protein-coding genes related to diseases of the immune and nervous systems and tumoral processes. Notably, CD5 and VPS37C, linked to immune function, were significantly associated with long COVID in men. Our results suggest that persistent immune dysregulation may be involved in the development of precisely defined long COVID. 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