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.

中文翻译：

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通过整合人类蛋白质组和遗传学来鉴定颅内动脉瘤中新的风险基因


全基因组关联研究 （GWAS） 在检测与颅内动脉瘤 （IA） 相关的众多基因座方面越来越受欢迎，但这些基因座的功能尚不清楚。在这项研究中，我们采用了综合分析管道来有效地改变遗传关联并鉴定 IA 的新基因。使用多维高通量数据，我们整合了蛋白质组范围关联研究 （PWAS）、转录组范围关联研究 （TWAS）、孟德尔随机化 （MR） 和贝叶斯共定位分析，以优先考虑可以通过改变大脑和血液中的表达和蛋白质丰度来增加 IA 风险的基因。此外，对 Willis 环进行单细胞 RNA 测序 （scRNA-seq） 以富集细胞中的过滤基因，并使用 IA 的大量 RNA-seq 数据对每个基因进行基因集富集分析 （GSEA）。没有证明具有顺式调节血浆蛋白水平的显著基因与 IA 相关。发现大脑中 5 个基因的蛋白质丰度与 IA 相关。根据细胞富集分析，这 5 个基因主要在内皮细胞、成纤维细胞和血管平滑肌细胞中表达。只有 CNNM2 、 GPRIN3 和 UFL1 三个基因通过了 MR 和贝叶斯共定位分析。虽然 UFL1 由于未进行剖分而未在确认 PWAS 中得到验证，但它在 TWAS 中得到了验证。GSEA 表明这三个基因与细胞周期有关。此外，发现 CNNM2 的蛋白质丰度与 IA 破裂相关 （基于 PWAS、MR 和共定位分析）。 我们的研究结果表明，CNNM2、GPRIN3 和 UFL1 （CNNM2 与 IA 破裂相关） 是潜在的 IA 风险基因，可能为未来研究 IA 的可能机制和治疗靶点提供广泛线索。