Novel Genome-wide Interactions Mediated via BOLL and EDNRA Polymorphisms in Intracranial Aneurysm
Abstract Association of boule (BOLL) and endothelin receptor type A (EDNRA) loci with intracranial aneurysm (IA) formation has been reported via genome-wide association studies. However, the underlying genome-wide interactions have yet to be reported. We sought to identify genome-wide interactions involving BOLL and EDNRA loci for IA. Genome-wide interaction analyses of BOLL and EDNRA involving 250 IA patients and 296 controls were performed under an additive effect model. Subsequent gene expression analyses were conducted using transcripts per million (TPM). A total of 23 and 11 SNPs suggested a genome-wide threshold (p < 1.25×10−8) interacting with rs700651 (BOLL) and rs6841581 (EDNRA), respectively. The rs1105980 (PTCH1) showed the most significant interaction with rs700651 (p = 6.41×10−11). The rs74585958 (RYK) interacted strongly with rs6841581 (p = 1.64×10−9). The BOLL-interacting CXCR4 was highly overexpressed in whole blood (TPM = 419.8) and CCDC3 was overexpressed in all artery-related tissues (TPM = 315.4 to 473.9). EDNRA-interacting EIF4H showed a comprehensively elevated expression across all tissues and cells (TPM = 85.8 to 372.0). Genome-wide interaction study shows that BOLL and EDNRA may contribute to IA formation by interacting with multiple genes in cardio-metabolic pathway. Our findings may provide insight into the functional relevant to IA susceptibility.