TY - JOUR
TI - 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,
AU - Elvira
AU - Hiltunen, Sini
AU - Lindgren, Erik
AU - Margaglione, Maurizio
AU - and Duchez, Veronique Le Cam
AU - Triquenot, Aude Bagan
AU - Zedde,
AU - Marialuisa
AU - Mancuso, Michelangelo
AU - Ruigrok, Ynte M.
AU - Marjot,
AU - Thomas
AU - Worrall, Brad
AU - Majersik, Jennifer J.
AU - Metso, Tiina M.
AU - and Putaala, Jukka
AU - Haapaniemi, Elena
AU - Zuurbier, Susanna M. and
AU - Brouwer, Matthijs C.
AU - Passamonti, Serena M.
AU - Abbattista, Maria and
AU - Bucciarelli, Paolo
AU - Mitchell, Braxton D.
AU - Kittner, Steven J. and
AU - Lemmens, Robin
AU - Jern, Christina
AU - Pappalardo, Emanuela
AU - Costa,
AU - Paolo
AU - Colombi, Marina
AU - de Sousa, Diana Aguiar
AU - Rodrigues,
AU - Sofia
AU - Canhao, Patricia
AU - Tkach, Aleksander
AU - Santacroce, Rosa
AU - and Favuzzi, Giovanni
AU - Arauz, Antonio
AU - Colaizzo, Donatella and
AU - Spengos, Kostas
AU - Hodge, Amanda
AU - Ditta, Reina
AU - Pezzini,
AU - Alessandro
AU - Debette, Stephanie
AU - Coutinho, Jonathan M.
AU - Thijs,
AU - Vincent
AU - Jood, Katarina
AU - Pare, Guillaume
AU - Tatlisumak, Turgut
AU - and Ferro, Jose M.
AU - Sharma, Pankaj
JO - Annals of Neurology
PY - 2021
VL - 90
TODO - 5
SP - 777-788
PB - Wiley
SN - 0364-5134, 1531-8249
TODO - 10.1002/ana.26205
TODO - null
TODO - 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 x 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 x 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 x 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
ER -