A Genome-Wide Investigation of Copy Number Variation in Patients with Sporadic Brain Arteriovenous Malformation

Abstract

BackgroundBrain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFβ) signaling pathway.MethodsTo investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM.ResultsA CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10−9); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM.ConclusionWe did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.

Genomic copy number variation analysis in multiple system atrophy

“…The results of GO analyses indicated an association with MSA that differed from the results obtained in studies of other diseases [ 26 , 38 – 40 ]. The GO results of CNVs in intronic regions were more closely related to the molecular mechanism of MSA than those of CNVs in exonic regions.…”

Genome-wide association study of sporadic brain arteriovenous malformations

“…Several of the top GWAS hits implicated genes involved in vascular biology and may represent smaller effects that we were not powered to reliably detect. Taken together with our previous copy number variation analysis, 41 these results suggest that common genetic variation is not a major risk factor for BAVM in Caucasians. Other potential genetic mechanisms may nonetheless contribute to sporadic BAVM, including modest effect common variants, such as the six suggestive but non-significant loci revealed by our replication analysis, rare genetic variants, or somatic or epigenetic variation.…”

Are parenchymal AVMs congenital lesions?

“…6 A CNV was identified on initial screening but did not replicate in an independent cohort of patients. 6 Similarly, no association was found between rare CNVs and disease susceptibility. 6 However, larger, well-powered studies might be able to detect significant associations.…”

“…6 Similarly, no association was found between rare CNVs and disease susceptibility. 6 However, larger, well-powered studies might be able to detect significant associations.…”