Introduction: Genome-wide association studies (GWAS) have identified many common variants (SNPs) associated with Intracranial Aneurysms (IA) but the causal genes, pathways and the biological mechanism remains unknown. Given that pathogenic processes are cell-specific and most association signals lie in noncoding regions, integrating genetic variation associated with gene expression changes from relevant primary cells may be important for overcoming these challenges.
Methods: We have performed a genome-wide expression and splicing quantitative trait locus (eQTL and sQTL) study of highly purified T-cells and CD14+CD16- monocytes from gene expression studies of 461 healthy individuals of European, African American and East Asian ancestry.
Results: Amongst genetically mapped traits, we observed that susceptibility alleles for IA affect gene expression and splicing of nearby genes in both monocytes and T-lymphocytes. Specifically, we identified 7 IA associated SNPs that are cis-eQTLs in monocyte- and T-cells. Using a Bayesian colocalization method, we demonstrated that at least 5 of these are likely to be truly driven by regulatory effects and thus, likely to be the candidate causal genes (NT5C2, BET1L, FGD6, ANKRD44, and SF3B1).
Conclusions: Overall, this study identifies many novel cis eQTLs that functionally implicate an immune cell type in genetic susceptibility to intracranial aneurysms illustrating the complexity of understanding the cell-specific functional consequences of genetic susceptibility to human disease. Future fine-mapping and functional studies will explore the mechanism by which these cis-eQTLs are associated with IA pathology
Patient Care: This study identifies potential candidate genes involved in the pathophysiology of intracranial aneurysm formation. Based on this study, a drug could be developed that would inhibit the driving networks and molecular pathways involved in aneurysms formation. In addition, blood biomarkers of aneurysms can be developed based on the gene expression data.
Learning Objectives: By the conclusion of this session, participants should be able to:
1)describe the importance GWAS studies in identifying the genetic variants associated in intracranial aneurysms formation.
2) Discuss the candidate causal genes (NT5C2, BET1L, FGD6, ANKRD44, and SF3B1) involved in aneurysm formation.
References: 1. Yasuno K et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet. 2010 May;42(5):420-5. doi: 10.1038/ng.563.
2. Bilguvar K et al. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet. 2008 Dec;40(12):1472-7. doi: 10.1038/ng.240.
3. Chen J et al. A functional variant of the collagen type III alpha1 gene modify risk of sporadic intracranial aneurysms.Hum Genet. 2012 Jul;131(7):1137-43. doi: 10.1007/s00439-012-1138-6.