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Research paper
Genome-wide association study of sporadic brain arteriovenous malformations
  1. Shantel Weinsheimer1,
  2. Nasrine Bendjilali2,
  3. Jeffrey Nelson3,
  4. Diana E Guo3,
  5. Jonathan G Zaroff4,
  6. Stephen Sidney4,
  7. Charles E McCulloch5,
  8. Rustam Al-Shahi Salman6,
  9. Jonathan N Berg7,
  10. Bobby P C Koeleman8,
  11. Matthias Simon9,
  12. Azize Bostroem9,
  13. Marco Fontanella10,
  14. Carmelo L Sturiale11,
  15. Roberto Pola12,
  16. Alfredo Puca11,
  17. Michael T Lawton13,
  18. William L Young3,
  19. Ludmila Pawlikowska3,14,
  20. Catharina J M Klijn15,
  21. Helen Kim3,5,14
  22. on behalf of the GEN-AVM Consortium
  1. 1Mental Health Center, Sct. Hans MHS—Capital Region of Denmark, Institute of Biological Psychiatry, Roskilde, Denmark
  2. 2Department of Mathematics, Rowan University, Glassboro, New Jersey, USA
  3. 3Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California, USA
  4. 4Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA
  5. 5Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
  6. 6Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
  7. 7Department of Clinical Genetics, University of Dundee, Dundee, UK
  8. 8Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
  9. 9Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany
  10. 10Division of Neurosurgery, University of Torino, University of Brescia, Brescia, Italy
  11. 11Institute of Neurosurgery, Catholic University of Rome, Rome, Italy
  12. 12Institute of Medicine, Catholic University of Rome, Rome, Italy
  13. 13Department of Neurological Surgery, University of California, San Francisco, California, USA
  14. 14Institute for Human Genetics, University of California, San Francisco, California, USA
  15. 15Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
  1. Correspondence to Dr Helen Kim, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, P.O. Box 1363, San Francisco, CA, 94143, USA; Helen.Kim2{at}


Background 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.

Methods 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.

Results 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.

Conclusions 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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