- •Cerebral vein thrombosis (CVT) is a rare life-threatening disease.
- •Genetic risk factors for CVT are still largely unknown.
- •We performed NGS of 734 hemostatic genes in 171 CVT patients and 298 controls.
- •We identified a common variant rs8176719 in the ABO gene associated with CVT.
Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown.
To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS).
We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants.
We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52–2.73; P = 2.07 × 10−6; Bonferroni P = 0.008). In addition, we identified 8839 rare variants (MAF ≤ 1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT.
Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT.
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Published online: June 15, 2018
Accepted: June 13, 2018
Received in revised form: May 16, 2018
Received: January 12, 2018
© 2018 Elsevier Ltd. All rights reserved.