title: Genome-wide association study of sporadic brain arteriovenous malformations.
abstract: The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium.
  
  
  
  The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls.
  
  
  
  The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort.
  
  
  
  We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution.
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authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Rustam
authors.identifier: 0000-0002-2108-9222
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authors.affiliation: Department of Clinical Genetics, University of Dundee, Dundee, UK.
authors.forename: Jonathan N
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authors.affiliation: Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
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authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Azize
authors.initials: A
authors.lastname: Bostroem
authors.affiliation: Division of Neurosurgery, University of Torino, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fontanella
authors.affiliation: Institute of Neurosurgery, Catholic University of Rome, Rome, Italy.
authors.forename: Carmelo L
authors.initials: CL
authors.lastname: Sturiale
authors.affiliation: Institute of Medicine, Catholic University of Rome, Rome, Italy.
authors.forename: Roberto
authors.initials: R
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authors.affiliation: Institute of Neurosurgery, Catholic University of Rome, Rome, Italy.
authors.forename: Alfredo
authors.initials: A
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authors.initials: MT
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authors.initials: WL
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authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California, USA Institute for Human Genetics, University of California, San Francisco, California, USA.
authors.forename: Ludmila
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authors.lastname: Pawlikowska
authors.affiliation: Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Catharina J M
authors.initials: CJ
authors.lastname: Klijn
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California, USA Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA Institute for Human Genetics, University of California, San Francisco, California, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People
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