颅内动脉瘤的遗传结构解剖。

IF 6 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation: Genomic and Precision Medicine Pub Date : 2025-04-21 DOI:10.1161/CIRCGEN.123.004626

Shaunak S Adkar, Julie Lynch, Ryan B Choi, Tanmoy Roychowdhury, Renae L Judy, Kaavya Paruchuri, Dong-Chuan Go, Sharika Bamezai, John Cabot, Sabina Sorondo, Michael G Levin, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Saiju Pyarajan, Kyong-Mi Chang, Scott Damrauer, Phil Tsao, Stephen Skirboll, Nicholas J Leeper, Derek Klarin

{"title":"颅内动脉瘤的遗传结构解剖。","authors":"Shaunak S Adkar, Julie Lynch, Ryan B Choi, Tanmoy Roychowdhury, Renae L Judy, Kaavya Paruchuri, Dong-Chuan Go, Sharika Bamezai, John Cabot, Sabina Sorondo, Michael G Levin, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Saiju Pyarajan, Kyong-Mi Chang, Scott Damrauer, Phil Tsao, Stephen Skirboll, Nicholas J Leeper, Derek Klarin","doi":"10.1161/CIRCGEN.123.004626","DOIUrl":null,"url":null,"abstract":"Background: The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.Methods: We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.Results: We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; P=8.8×10-17), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; P=1.2×10-3), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; P=1.0×10-4) ancestries.Conclusions: Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004626"},"PeriodicalIF":6.0000,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dissecting the Genetic Architecture of Intracranial Aneurysms.\",\"authors\":\"Shaunak S Adkar, Julie Lynch, Ryan B Choi, Tanmoy Roychowdhury, Renae L Judy, Kaavya Paruchuri, Dong-Chuan Go, Sharika Bamezai, John Cabot, Sabina Sorondo, Michael G Levin, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Saiju Pyarajan, Kyong-Mi Chang, Scott Damrauer, Phil Tsao, Stephen Skirboll, Nicholas J Leeper, Derek Klarin\",\"doi\":\"10.1161/CIRCGEN.123.004626\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Background: The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.Methods: We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.Results: We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; P=8.8×10-17), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; P=1.2×10-3), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; P=1.0×10-4) ancestries.Conclusions: Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.\",\"PeriodicalId\":10326,\"journal\":{\"name\":\"Circulation: Genomic and Precision Medicine\",\"volume\":\" \",\"pages\":\"e004626\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2025-04-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Genomic and Precision Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCGEN.123.004626\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Genomic and Precision Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCGEN.123.004626","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

摘要

背景：颅内动脉瘤（IA）发展的遗传风险归因于吸烟暴露和高血压的遗传风险。IA与其他心血管特征的关系以及IA风险位点对脑血管细胞类型中异常基因程序的贡献尚不清楚。方法：我们在百万退伍军人计划和芬兰队列研究中进行了一项全基因组关联研究，测试了欧洲、非洲和西班牙血统个体中大约2500万个DNA变异与未破裂IA（4694例和877091例对照）的关联。利用公开的汇总统计数据进行荟萃分析，产生了15 438例病例和1 183 973例对照的最终队列。我们构建了脑血管单核RNA测序数据集，并整合了IA汇总统计来优先考虑候选的因果细胞类型。我们构建了一个多基因风险评分来识别有发生IA风险的患者。结果：我们发现了5个与IA相关的新基因，将已知的易感位点数量增加到22个。在这些易感位点上，我们优先排序了17个候选致病基因。我们发现IA与冠状动脉疾病和腹主动脉瘤有显著的正遗传相关。IA基因集与脑血管单核RNA测序数据的整合揭示了与周细胞和平滑肌细胞的显著关联。最后，在整个欧洲，多基因风险评分与IA显著相关(优势比为1.87 [95% CI, 1.61-2.17]；P=8.8×10-17)，非洲人(优势比1.62 [95% CI, 1.19-2.15]；P=1.2×10-3)和西班牙裔(优势比2.28 [95% CI, 1.47-3.38]；4 P = 1.0×打败)祖先。结论：在这里，我们确定了5个与IA相关的新位点。汇总统计与脑血管单核RNA测序的整合揭示了参与基质生产的细胞类型的关联。我们验证了预测IA的多基因风险评分，控制了包括吸烟状况和血压在内的人口统计学变量。我们的研究结果表明，基质产生的缺陷可能驱动IA的发病机制独立于高血压和吸烟。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Dissecting the Genetic Architecture of Intracranial Aneurysms.

Background: The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.

Methods: We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.

Results: We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; P=8.8×10^-¹⁷), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; P=1.2×10^-³), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; P=1.0×10^-⁴) ancestries.

Conclusions: Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

9.20

自引率

5.40%

发文量

144

期刊介绍： Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.