d1c2412f2506f24b847227d5db043333 pmc_10487930.pdf 79b9b2f4ee623a7b53e80cf64fb84c8b4f79eb22 pmc_10487930.pdf 3d12083258d1c8be55a1418f44533b8fa643167951594ea3f6d2a35cfcb9b344 pmc_10487930.pdf Title: Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes Subject: We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection. Keywords: COVID-19; ischaemic stroke; GWAS; local genetic correlation; PRS Author: Laia Llucià-Carol, Elena Muiño, Natalia Cullell, Jara Cárcel-Márquez, Miquel Lledós, Cristina Gallego-Fabrega, Jesús Martin-Campos, Joan Martí-Fàbregas, Ana Aguilera-Simón, Anna M. Planas, Marta L. DeDiego, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastián García-Madrona, Tomás Segura, Esther González-Villar, Gemma Serrano-Heras, Ana Domínguez Mayoral, Paloma Menéndez-Valladares, Joan Montaner, Isabelle Migeotte, Souad Rahmouni, Gilles Darcis, David Bernardo, Silvia Rojo, Eva C. Schulte, Ulrike Protzer, Lisa Fricke, Christof Winter, Mari E. K. Niemi, Mattia Cordioli, Pilar Delgado and Israel Fernández-Cadenas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Aug 30 11:49:34 2023 CEST ModDate: Wed Aug 30 11:51:38 2023 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2623072 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- PXJXAS+VnURWPalladioL Type 1 Custom yes yes no 10 0 WFHGPY+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 PYCNXO+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 AWUDIK+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 UQZHSH+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 SOSCBV+CMSY10 Type 1 Builtin yes yes no 71 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 82 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-05-07 04:23:09 CEST RepresentationInformation: pmc_10487930.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-04-24 02:39:32 CEST Size: 2623072 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 371 FreeObjects: 5 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Local Genetic Covariance Estimation Destination: subsection.2.1 Item: Title: Polygenic Risk Score Destination: subsection.2.2 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Cohorts’ Description Destination: subsection.4.1 Item: Title: Genotyping Destination: subsection.4.2 Item: Title: Genotyped Data Quality Controls Destination: subsection.4.3 Item: Title: Genome-Wide Association Analysis Destination: subsection.4.4 Item: Title: Local Genetic Covariance Estimation Destination: subsection.4.5 Item: Title: Polygenic Risk Score Destination: subsection.4.6 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes Author: Laia Llucià-Carol, Elena Muiño, Natalia Cullell, Jara Cárcel-Márquez, Miquel Lledós, Cristina Gallego-Fabrega, Jesús Martin-Campos, Joan Martí-Fàbregas, Ana Aguilera-Simón, Anna M. Planas, Marta L. DeDiego, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastián García-Madrona, Tomás Segura, Esther González-Villar, Gemma Serrano-Heras, Ana Domínguez Mayoral, Paloma Menéndez-Valladares, Joan Montaner, Isabelle Migeotte, Souad Rahmouni, Gilles Darcis, David Bernardo, Silvia Rojo, Eva C. Schulte, Ulrike Protzer, Lisa Fricke, Christof Winter, Mari E. K. Niemi, Mattia Cordioli, Pilar Delgado and Israel Fernández-Cadenas Subject: We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection. 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