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.
| Original language | English |
|---|---|
| Pages (from-to) | 777-788 |
| Number of pages | 12 |
| Journal | Annals of neurology |
| Volume | 90 |
| Issue number | 5 |
| Early online date | 2021 |
| DOIs | |
| Publication status | Published - Nov 2021 |
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In: Annals of neurology, Vol. 90, No. 5, 11.2021, p. 777-788.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis
AU - Ken-Dror, Gie
AU - Cotlarciuc, Ioana
AU - Martinelli, Ida
AU - Grandone, Elvira
AU - Hiltunen, Sini
AU - Lindgren, Erik
AU - Margaglione, Maurizio
AU - Duchez, Veronique Le Cam
AU - Triquenot, Aude Bagan
AU - Zedde, Marialuisa
AU - Mancuso, Michelangelo
AU - Ruigrok, Ynte M.
AU - Marjot, Thomas
AU - Worrall, Brad
AU - Majersik, Jennifer J.
AU - Metso, Tiina M.
AU - Putaala, Jukka
AU - Haapaniemi, Elena
AU - Zuurbier, Susanna M.
AU - Brouwer, Matthijs C.
AU - Passamonti, Serena M.
AU - Abbattista, Maria
AU - Bucciarelli, Paolo
AU - Mitchell, Braxton D.
AU - Kittner, Steven J.
AU - Lemmens, Robin
AU - Jern, Christina
AU - Pappalardo, Emanuela
AU - Costa, Paolo
AU - Colombi, Marina
AU - de Sousa, Diana Aguiar
AU - Rodrigues, Sofia
AU - Canhão, Patrícia
AU - Tkach, Aleksander
AU - Santacroce, Rosa
AU - Favuzzi, Giovanni
AU - Arauz, Antonio
AU - Colaizzo, Donatella
AU - Spengos, Kostas
AU - Hodge, Amanda
AU - Ditta, Reina
AU - Pezzini, Alessandro
AU - Debette, Stephanie
AU - Coutinho, Jonathan M.
AU - Thijs, Vincent
AU - Jood, Katarina
AU - Pare, Guillaume
AU - Tatlisumak, Turgut
AU - Ferro, José M.
AU - Sharma, Pankaj
N1 - Funding Information: This work is presented on behalf of the International Stroke Genetics Consortium (ISGC) & the Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) collaborators. We are grateful to our patients for allowing us to enter them into this collaboration without whom this work would not have been possible. This study was supported by grants awarded to P.S. from the Stroke Association (UK), the Dowager Countess Eleanor Peel Trust (UK), and the Interreg 2 Seas program 2014-2020, cofunded by the European Regional Development Fund under subsidy contract 2S01-059_IMODE. P.S. was funded by a Department of Health (UK) Senior Fellowship at Imperial College London for part of this study. The cohort of 231 French cases was constituted during a hospital protocol of clinical research approved by the French Ministry of Health; biological collection was kept and managed by INSERM CIC-CRB 1404, F-76000 Rouen, France. The controls from Belgium were genotyped as part of the SIGN study. R.L. is a senior clinical investigator of FWO Flanders. T.T. is the recipient of funding from the Sigrid Juselius Foundation (Finland), Helsinki University Central Hospital (Finland), Sahlgrenska University Hospital (Sweden), and University of Gothenburg (Sweden). The Swedish Research Council (2018-02543) and the Swedish Heart and Lung Foundation (20190203) also supported the study. J.M.C. has received funding from the Dutch Thrombosis Foundation. This material is the result of work supported with resources of and the use of facilities at the VA Maryland Health Care System, Baltimore, Maryland, and was also supported in part by the National Institutes of Health (U01NS069208, R01NS105150, R01NS100178). The contents do not represent the views of the US Department of Veterans Affairs or the US Government. We thank our patients for allowing us to enter them into this collaboration; without them, this work would not have been possible. Funding Information: This work is presented on behalf of the International Stroke Genetics Consortium (ISGC) & the Bio‐Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) collaborators. We are grateful to our patients for allowing us to enter them into this collaboration without whom this work would not have been possible. This study was supported by grants awarded to P.S. from the Stroke Association (UK), the Dowager Countess Eleanor Peel Trust (UK), and the Interreg 2 Seas program 2014‐2020, cofunded by the European Regional Development Fund under subsidy contract 2S01‐059_IMODE. P.S. was funded by a Department of Health (UK) Senior Fellowship at Imperial College London for part of this study. The cohort of 231 French cases was constituted during a hospital protocol of clinical research approved by the French Ministry of Health; biological collection was kept and managed by INSERM CIC‐CRB 1404, F‐76000 Rouen, France. The controls from Belgium were genotyped as part of the SIGN study. R.L. is a senior clinical investigator of FWO Flanders. T.T. is the recipient of funding from the Sigrid Juselius Foundation (Finland), Helsinki University Central Hospital (Finland), Sahlgrenska University Hospital (Sweden), and University of Gothenburg (Sweden). The Swedish Research Council (2018‐02543) and the Swedish Heart and Lung Foundation (20190203) also supported the study. J.M.C. has received funding from the Dutch Thrombosis Foundation. This material is the result of work supported with resources of and the use of facilities at the VA Maryland Health Care System, Baltimore, Maryland, and was also supported in part by the National Institutes of Health (U01NS069208, R01NS105150, R01NS100178). The contents do not represent the views of the US Department of Veterans Affairs or the US Government. Publisher Copyright: © 2021 American Neurological Association. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85115852311&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ana.26205
DO - https://doi.org/10.1002/ana.26205
M3 - Article
C2 - 34459509
SN - 0364-5134
VL - 90
SP - 777
EP - 788
JO - Annals of neurology
JF - Annals of neurology
IS - 5
ER -