Next-generation DNA sequencing to identify novel genetic risk factors for cerebral vein thrombosis

Marcin M. Gorski, Hugoline G. de Haan, Ilaria Mancini, Luca A. Lotta, Paolo Bucciarelli, Serena M. Passamonti, Andrea Cairo, Emanuela Pappalardo, Astrid van Hylckama Vlieg, Ida Martinelli, Frits R. Rosendaal, Flora Peyvandi

Research output: Contribution to journalArticlepeer-review


Background: 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. Aim: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)76-81
Number of pages6
JournalThrombosis Research
Publication statusPublished - Sep 1 2018


  • ABO blood group
  • Cerebral vein thrombosis
  • Next-generation DNA sequencing
  • rs8176719

ASJC Scopus subject areas

  • Hematology


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