Gie Ken-Dror1, Ioana Cotlarciuc1, Ida Martinelli2, Elvira Grandone3,4, Sini Hiltunen5, Erik Lindgren6,7, Maurizio Margaglione8, Veronique Le Cam Duchez9, Aude Bagan Triquenot10, Marialuisa Zedde11, Michelangelo Mancuso12, Ynte M Ruigrok13, Thomas Marjot14, Brad Worrall15, Jennifer J Majersik16, Tiina M Metso5, Jukka Putaala5, Elena Haapaniemi5, Susanna M Zuurbier17, Matthijs C Brouwer17, Serena M Passamonti2, Maria Abbattista2, Paolo Bucciarelli2, Braxton D Mitchell18,19, Steven J Kittner20,21, Robin Lemmens22, Christina Jern23,24, Emanuela Pappalardo2, Paolo Costa25, Marina Colombi26, Diana Aguiar de Sousa27, Sofia Rodrigues27, Patrícia Canhão27, Aleksander Tkach16, Rosa Santacroce8, Giovanni Favuzzi3, Antonio Arauz28, Donatella Colaizzo3, Kostas Spengos29, Amanda Hodge30, Reina Ditta30, Alessandro Pezzini25, Stephanie Debette31, Jonathan M Coutinho17, Vincent Thijs32, Katarina Jood6,7, Guillaume Pare30, Turgut Tatlisumak5,6,7, José M Ferro27, Pankaj Sharma1,33. 1. Institute of Cardiovascular Research Royal Holloway, University of London (ICR2UL), London, UK. 2. Fondazione IRCCS Ca'Granda - Ospedale Maggiore Policlinico, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy. 3. Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Home for the Relief of Suffering, S. Giovanni Rotondo, Foggia, Italy. 4. Obstetrics/Gynecology Department, First I. M. Sechenov Moscow State Medical University, Moscow, Russia. 5. Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. 6. Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. 7. Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden. 8. Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy. 9. Normandy University, UNIROUEN, INSERM U1096, Rouen University Hospital, Vascular Hemostasis Unit and INSERM CIC-CRB 1404, Rouen, France. 10. Department of Neurology, Rouen University Hospital, Rouen, France. 11. Neurology Unit, Stroke Unit, Local Health Unit-IRCCS of Reggio Emilia, Reggio Emilia, Italy. 12. Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Italy. 13. UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands. 14. Oxford Liver Unit, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 15. Department of Neurology, University of Virginia, Charlottesville, VA. 16. Department of Neurology, University of Utah, Salt Lake City, UT. 17. Department of Neurology, Amsterdam University Medical Centers, location AMC, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, the Netherlands. 18. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. 19. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD. 20. Department of Neurology, University of Maryland School of Medicine, Baltimore, MD. 21. Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD. 22. Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven; VIB Center for Brain & Disease Research; Department of Neurology, University Hospitals Leuven, Leuven, Belgium. 23. Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 24. Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden. 25. Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy. 26. Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy. 27. Department of Neurosciences, Hospital of Santa Maria, University of Lisbon, Lisbon, Portugal. 28. Stroke Clinic, National Institute of Neurology and Neurosurgery Manuel Velasco Suarez, Mexico City, Mexico. 29. Department of Neurology, University of Athens School of Medicine, Eginition Hospital, Athens, Greece. 30. McMaster University, Pathology and Molecular Medicine, Population Health Research Institute and Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada. 31. Department of Neurology, Bordeaux University Hospital, Bordeaux University, Bordeaux, France. 32. Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia. 33. Department of Clinical Neuroscience, Imperial College Healthcare NHS Trust, London, UK.
Abstract
OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.
OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.
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Authors: Yu-Ching Cheng; Tara M Stanne; Anne-Katrin Giese; Weang Kee Ho; Matthew Traylor; Philippe Amouyel; Elizabeth G Holliday; Rainer Malik; Huichun Xu; Steven J Kittner; John W Cole; Jeffrey R O'Connell; John Danesh; Asif Rasheed; Wei Zhao; Stefan Engelter; Caspar Grond-Ginsbach; Yoichiro Kamatani; Mark Lathrop; Didier Leys; Vincent Thijs; Tiina M Metso; Turgut Tatlisumak; Alessandro Pezzini; Eugenio A Parati; Bo Norrving; Steve Bevan; Peter M Rothwell; Cathie Sudlow; Agnieszka Slowik; Arne Lindgren; Matthew R Walters; Jim Jannes; Jess Shen; David Crosslin; Kimberly Doheny; Cathy C Laurie; Sandip M Kanse; Joshua C Bis; Myriam Fornage; Thomas H Mosley; Jemma C Hopewell; Konstantin Strauch; Martina Müller-Nurasyid; Christian Gieger; Melanie Waldenberger; Annette Peters; Christine Meisinger; M Arfan Ikram; W T Longstreth; James F Meschia; Sudha Seshadri; Pankaj Sharma; Bradford Worrall; Christina Jern; Christopher Levi; Martin Dichgans; Giorgio B Boncoraglio; Hugh S Markus; Stephanie Debette; Arndt Rolfs; Danish Saleheen; Braxton D Mitchell Journal: Stroke Date: 2016-01-05 Impact factor: 7.914
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