PT - JOURNAL ARTICLE AU - Wu, Jinghao AU - Mei, Yunyun AU - Li, XinYu AU - Yu, Wen-Kai AU - Zhou, Zi Han AU - Yang, Yinghao AU - Niu, Pengpeng AU - Wang, Yunchao AU - Shi, Chang-He AU - Zhu, Hanghang AU - He, Wenjun AU - Gao, Yuan AU - Xu, Yuming AU - Li, Yusheng TI - PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis AID - 10.1136/svn-2023-003076 DP - 2024 Aug 23 TA - Stroke and Vascular Neurology PG - svn-2023-003076 4099 - http://svn.bmj.com/content/early/2024/08/23/svn-2023-003076.short 4100 - http://svn.bmj.com/content/early/2024/08/23/svn-2023-003076.full AB - Background Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms.Methods We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network.Results Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort.Conclusions This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.All data relevant to the study are included in the article or uploaded as supplementary information.