Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics

基因 生物 孟德尔随机化 转录组 全基因组关联研究 计算生物学 蛋白质组 遗传学 候选基因 遗传关联 基因表达 单核苷酸多态性 遗传变异 基因型
作者
Congyan Wu,Hanchen Liu,Qiao Zuo,Aimin Jiang,Chuanchuan Wang,Nan Lv,Ruyue Lin,Yonghui Wang,Kang Zong,Yanpeng Wei,Qinghai Huang,Qiang Li,Pengfei Yang,Rui Zhao,Jianmin Liu
出处
期刊:Brain [Oxford University Press]
卷期号:147 (8): 2817-2825 被引量:5
标识
DOI:10.1093/brain/awae111
摘要

Abstract Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these loci function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes for IA. Using multidimensional high-throughput data, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR) and Bayesian co-localization analyses to prioritize genes that can increase IA risk by altering their expression and protein abundances in the brain and blood. Moreover, single-cell RNA sequencing (scRNA-seq) of the circle of Willis was performed to enrich filtered genes in cells, and gene set enrichment analysis (GSEA) was conducted for each gene using bulk RNA-seq data for IA. No significant genes with cis-regulated plasma protein levels were proven to be associated with IA. The protein abundances of five genes in the brain were found to be associated with IA. According to cellular enrichment analysis, these five genes were expressed mainly in the endothelium, fibroblasts and vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 and UFL1, passed MR and Bayesian co-localization analyses. While UFL1 was not validated in confirmation PWAS as it was not profiled, it was validated in TWAS. GSEA suggested these three genes are associated with the cell cycle. In addition, the protein abundance of CNNM2 was found to be associated with IA rupture (based on PWAS, MR and co-localization analyses). Our findings indicated that CNNM2, GPRIN3 and UFL1 (CNNM2 correlated with IA rupture) are potential IA risk genes that may provide a broad hint for future research on possible mechanisms and therapeutic targets for IA.
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