Abstract 109: Biological Pathways Enriched For Genes Associated With Lesion Burden In Cerebral Cavernous Malformation

Introduction: Familial Cerebral Cavernous Malformation (CCM) is an autosomal dominant disorder caused by mutations in KRIT1 , CCM2 and PDCD10 . CCMs can result in seizures, neurological deficits, and intracranial hemorrhage. Our prior research identified genetic modifiers that contribute to CCM progression. We hypothesized that genes associated with CCM progression (lesion burden, large lesion size, and hemorrhage) are enriched in biological pathways. We performed a functional enrichment analysis of top associated genes from a genome-wide panel to identify pathways that, when dysregulated, may contribute to CCM progression. Methods: Familial CCM cases (n=335) enrolled in the Brain Vascular Malformation Consortium were genotyped using Affymetrix Axiom Genome-Wide LAT1 Human Arrays. Logistic regression analysis was performed using an additive model, adjusting for age at enrollment and sex, to identify genetic variants associated with total lesion burden, large lesion burden (≥5mm), or hemorrhage. For nominally associated variants (P<0.001) mapping +/-5kb to genes, we performed an over-representation analysis using WebGestalt to identify enrichment of genes in KEGG biological pathways using a false discovery rate (FDR) < 0.15. Results: Our CCM GWAS study identified genes nominally associated with total lesion burden (n=298), large lesion burden (n=287), and hemorrhage (n=200). We found no significantly over-represented pathways for genes associated with large lesion burden and hemorrhage. However, six pathways were enriched for genes associated with total lesion burden, all with FDR=0.12: oxytocin signaling, synaptic vesicle cycle, HIF-1 signaling, neomycin, kanamycin and gentamicin biosynthesis, adrenergic signaling in cardiomyocytes, and gastric acid secretion. Interestingly, the HIF-1 pathway interacts with several pathways of interest in CCM, e.g., mTOR and PI3K-Akt. Conclusions: Genetic variants associated with total lesion burden in familial CCM map to genes that are likely enriched in KEGG biological pathways. These findings expand the list of candidate genetic modifiers for CCM lesion progression, including genes in the HIF-1 pathway, and necessitate further investigation in other independent CCM patient cohorts.