TY - JOUR
T1 - Genome-wide association study of sporadic brain arteriovenous malformations
AU - Weinsheimer, Shantel
AU - Bendjilali, Nasrine
AU - Nelson, Jeffrey
AU - Guo, Diana E.
AU - Zaroff, Jonathan G.
AU - Sidney, Stephen
AU - McCulloch, Charles E.
AU - Al-Shahi Salman, Rustam
AU - Berg, Jonathan N.
AU - Koeleman, Bobby P.C.
AU - Simon, Matthias
AU - Bostroem, Azize
AU - Fontanella, Marco
AU - Sturiale, Carmelo L.
AU - Pola, Roberto
AU - Puca, Alfredo
AU - Lawton, Michael T.
AU - Young, William L.
AU - Pawlikowska, Ludmila
AU - Klijn, Catharina J.M.
AU - Kim, Helen
N1 - Funding Information:
USA studies: NIH grants P01 NS044155, R01 NS034949, K23 NS058357 for AVM cases and controls; P50 NS2372 and U19 AI063603 for shared GWAS control data. The Netherlands AVM cohort: Van Leersum Fund, Royal Netherlands Academy of Arts and Sciences; a grant from Running-for-Nona. CJMK is supported by a clinical established investigator grant from the Dutch Heart Foundation (2012T077) and ASPASIA grant from The Netherlands Organisation for Health Research and Development, ZonMw (015008048). German AVM study: Funded in part by grants to MS from the University of Bonn (BONFOR). Italian AVM cohorts: D1 intramural grant from the Catholic University School of Medicine, Rome, Italy; grants from the Ministero dell'Università e della Ricerca Scientifica (MURST) of Italy; intramural grant from the University of Brescia, Italy. SIVMS study: Supported by the Chief Scientist Office of the Scottish Government Health Department; project grant from The Stroke Association; MRC clinical training, clinician scientist and senior clinical fellowships to RA-SS. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475.
Publisher Copyright:
© 2016 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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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U2 - 10.1136/jnnp-2015-312272
DO - 10.1136/jnnp-2015-312272
M3 - Article
C2 - 26818729
AN - SCOPUS:84962204101
SN - 0022-3050
VL - 87
SP - 916
EP - 923
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 9
ER -