title: Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.
abstract: BACKGROUND
  In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM.
  
  
  METHODS
  We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method.
  
  
  RESULTS
  In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08).
  
  
  CONCLUSIONS
  Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: P H C
authors: PH
authors: Kremer
authors: Department of Biomedical Genetics and Complex Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: B P C
authors: BP
authors: Koeleman
authors: Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
authors: L
authors: L
authors: Pawlikowska
authors: Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA.
authors: S
authors: S
authors: Weinsheimer
authors: Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA.
authors: N
authors: N
authors: Bendjilali
authors: Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA.
authors: S
authors: S
authors: Sidney
authors: Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA.
authors: J G
authors: JG
authors: Zaroff
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: G J E
authors: http://orcid.org/0000-0001-8930-3953
authors: GJ
authors: Rinkel
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: L H
authors: LH
authors: van den Berg
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Y M
authors: YM
authors: Ruigrok
authors: Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: G A P
authors: GA
authors: de Kort
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: J H
authors: JH
authors: Veldink
authors: Department of Anesthesia, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, California, USA Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
authors: H
authors: H
authors: Kim
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: C J M
authors: CJ
authors: Klijn
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D027682:Cation Transport Proteins; D016213:Cyclins / Q000235:genetics; D004706:Endodeoxyribonucleases; D020690:GTPase-Activating Proteins; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D002532:Intracranial Aneurysm / Q000150:complications* / Q000235:genetics*; D002538:Intracranial Arteriovenous Malformations / Q000150:complications* / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics; D055760:SOXF Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C561518:CDKN2B antisense RNA, human; C558175:CNNM2 protein, human; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D016213:Cyclins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D055760:SOXF Transcription Factors; C473607:STARD13 protein, human; D025521:Tumor Suppressor Proteins; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human
keywords: CEREBROVASCULAR DISEASE; GENETICS; STROKE