AbstractCardiovascular diseases (CVDs) and cerebrovascular diseases (CeVDs) are closely related vascular diseases, sharing common cardiometabolic risk factors (RFs). Although pleiotropic genetic variants of these two diseases have been reported, their underlying pathological mechanisms are still unclear.

摘要心血管疾病（CVD）和脑血管疾病（CeVDs）是密切相关的血管疾病，具有共同的心脏代谢危险因素（RFs）。尽管已经报道了这两种疾病的多效性遗传变异，但其潜在的病理机制仍不清楚。

Leveraging GWAS summary data and using genetic correlation, pleiotropic variants identification, and colocalization analyses, we identified 11 colocalized loci for CVDs-CeVDs-BP (blood pressure), CVDs-CeVDs-LIP (lipid traits), and CVDs-CeVDs-cIMT (carotid intima-media thickness) triplets. No shared causal loci were found for CVDs-CeVDs-T2D (type 2 diabetes) or CVDs-CeVDs-BMI (body mass index) triplets.

利用GWAS汇总数据，并使用遗传相关性，多效性变异鉴定和共定位分析，我们确定了11个共定位基因座，用于CVDs CeVDs BP（血压），CVDs CeVDs LIP（脂质性状）和CVDs CeVDs cIMT（颈动脉内膜中层厚度）三联体。没有发现CVDs-CeVDs-T2D（2型糖尿病）或CVDs-CeVDs-BMI（体重指数）三胞胎的共有因果基因座。

The 11 loci were mapped to 12 genes, namely CASZ1, CDKN1A, TWIST1, CDKN2B, ABO, SWAP70, SH2B3, LRCH1, FES, GOSR2, RPRML, and LDLR, where both GOSR2 and RPRML were mapped to one locus. They were enriched in pathways related to cellular response to external stimulus and regulation of the phosphate metabolic process and were highly expressed in endothelial cells, epithelial cells, and smooth muscle cells.

这11个基因座被定位到12个基因，即CASZ1，CDKN1A，TWIST1，CDKN2B，ABO，SWAP70，SH2B3，LRCH1，FES，GOSR2，RPRML和LDLR，其中GOSR2和RPRML都被定位到一个基因座。它们富含与细胞对外部刺激的反应和磷酸盐代谢过程的调节有关的途径，并在内皮细胞，上皮细胞和平滑肌细胞中高度表达。

Multi-omics analysis revealed methylation of two genes (CASZ1 and LRCH1) may play a causal role in the genetic pleiotropy. Notably, these pleiotropic loci are highly enriched in the targets of antihypertensive drugs, which further emphasizes the role of the blood pressure regulation pathway in the shared etiology of CVDs and CeVDs..

多组学分析显示，两个基因（CASZ1和LRCH1）的甲基化可能在遗传多效性中起因果作用。值得注意的是，这些多效性基因座在抗高血压药物的靶标中高度富集，这进一步强调了血压调节途径在CVD和CEVD共同病因中的作用。。

IntroductionVascular diseases encompass a broad range of disorders of the heart and circulation in other organs. Among them, cardiovascular diseases (CVDs) and cerebrovascular diseases (CeVDs) are the two main types that occur in the heart and brain, respectively, and account for more than 80% of total deaths1.

引言血管疾病包括广泛的心脏疾病和其他器官的循环障碍。其中，心血管疾病（CVD）和脑血管疾病（CeVDs）分别是心脏和大脑中发生的两种主要类型，占总死亡人数的80%以上1。

CVDs mainly include coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF), while CeVDs mainly indicate stroke2. CVDs and CeVDs are closely related, caused by many shared cardiometabolic risk factors (RFs) and frequent coexistence3,4. Inherited DNA sequence variants play a role in conferring risk for CVDs and CeVDs5,6.Previous studies, including family history studies, genome-wide association studies (GWAS), and cross-trait analyses, reveal that CVDs and CeVDs may share genetic architectures.

心血管疾病主要包括冠状动脉疾病（CAD），心肌梗塞（MI），心力衰竭（HF）和心房颤动（AF），而CeVDs主要表示中风2。心血管疾病和CeVDs密切相关，由许多共同的心脏代谢危险因素（RFs）和频繁共存引起3,4。遗传的DNA序列变异在赋予CVD和CeVDs风险中起作用[6]。以前的研究，包括家族史研究，全基因组关联研究（GWAS）和交叉性状分析，表明CVD和CeVDs可能共享遗传结构。

For example, coronary heart disease (CHD) and ischemic stroke exhibit shared familial susceptibility, with a linkage between the family history of stroke to increased risks of CHD7,8,9. GWAS studies have shown three of the 42 genome-wide significant loci for CAD were related to ischemic stroke10. Chromosome 9p21, the most robust genetic marker of CHD, was also associated with stroke11.

。GWAS研究表明，CAD的42个全基因组重要基因座中有3个与缺血性中风有关10。染色体9p21是冠心病最强大的遗传标记，也与中风有关11。

Other loci associated with both diseases include SH2B3, ABO, DDAH1, etc.10,12. In recent decades, the emergence of GWAS data with large sample sizes, along with advanced analysis technologies, has positioned research on genetic sharing across traits as a key area of focus. Consequently, numerous studies have examined the genetic links among cardiovascular diseases.

与这两种疾病相关的其他基因座包括SH2B3，ABO，DDAH1等10,12。近几十年来，大样本量GWAS数据的出现以及先进的分析技术，使跨性状遗传共享的研究成为一个关键的重点领域。因此，许多研究已经检查了心血管疾病之间的遗传联系。

For instance, several studies have uncovered shared genes between CVDs and CeVDs through methods such as meta-analysis13, network module analysis14, and across-trait association a.

例如，一些研究通过荟萃分析13，网络模块分析14和跨性状关联a等方法发现了CVD和CEVD之间的共享基因。

Data availability

数据可用性

The datasets analyzed during the current study are freely available for download from the following URLs: GWAS summary data for CAD (https://www.ebi.ac.uk/gwas/studies/GCST90132314); GWAS summary data for MI (https://www.ebi.ac.uk/gwas/publications/33532862); GWAS summary data for HF (https://www.ebi.ac.uk/gwas/publications/31919418); GWAS summary data for AF (https://www.ebi.ac.uk/gwas/publications/29892015); GWAS summary data for AS and AIS (https://cd.hugeamp.org/dinspector.html?dataset=GWAS_MEGASTROKE_eu); GWAS summary data for SBP (https://www.ebi.ac.uk/gwas/publications/30224653); GWAS summary data for TG, LDL-C, HDL-C (https://csg.sph.umich.edu/willer/public/glgc-lipids2021/); GWAS summary data for T2D (https://diagram-consortium.org/); GWAS summary data for BMI (https://www.ebi.ac.uk/gwas/publications/30239722); GWAS summary data for c-IMT (https://www.ebi.ac.uk/gwas/publications/34852643).

当前研究期间分析的数据集可从以下URL免费下载：GWAS CAD摘要数据(https://www.ebi.ac.uk/gwas/studies/GCST90132314)；MI的GWAS摘要数据(https://www.ebi.ac.uk/gwas/publications/33532862)；HF的GWAS摘要数据(https://www.ebi.ac.uk/gwas/publications/31919418)(https://www.ebi.ac.uk/gwas/publications/29892015)；AS和AIS的GWAS汇总数据(https://cd.hugeamp.org/dinspector.html?dataset=GWAS_MEGASTROKE_eu)；GWAS SBP汇总数据(https://www.ebi.ac.uk/gwas/publications/30224653)；TG，LDL-C，HDL-C的GWAS汇总数据(https://csg.sph.umich.edu/willer/public/glgc-lipids2021/)；GWAS T2D汇总数据(https://diagram-consortium.org/)；GWAS BMI汇总数据(https://www.ebi.ac.uk/gwas/publications/30239722)；c-IMT的GWAS摘要数据(https://www.ebi.ac.uk/gwas/publications/34852643)。

LD scores and reference panel derived from 1000 Genomes phase 3, https://data.broadinstitute.org/alkesgroup/LDSCORE/; LD scores and reference panel derived from 1,029,876 QCed UK Biobank imputed HapMap3 SNPs (https://github.com/zhenin/HDL/wiki/Reference)..

LD分数和参考面板来自1000个基因组第3阶段，https://data.broadinstitute.org/alkesgroup/LDSCORE/；LD分数和参考面板来自1029876个QCed英国生物库估算的HapMap3 SNP(https://github.com/zhenin/HDL/wiki/Reference)。。

Code availability

代码可用性

All code used in this project is available at https://doi.org/10.5281/zenodo.1427997292.

本项目中使用的所有代码均可在https://doi.org/10.5281/zenodo.1427997292.

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Ding, K. Shared Genetic Etiology of CVDs and CeVDs through RFs https://doi.org/10.5281/zenodo.14279972 (2024).Download referencesAcknowledgementsThis work was supported by the High-performance Computing Platform of Peking University. This research was funded by the National Natural Science Foundation of China (No.

丁，K。通过RFs共享CVD和CEVD的遗传病因https://doi.org/10.5281/zenodo.14279972（2024年）。下载参考文献致谢这项工作得到了北京大学高性能计算平台的支持。本研究由国家自然科学基金资助（No。

82073642).Author informationAuthor notesThese authors jointly supervised this work: Xueying Qin, Yiqun Wu.Authors and AffiliationsDepartment of Epidemiology and Biostatistics, School of Public Health, Peking University; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, ChinaKexin Ding, Xueying Qin, Huairong Wang, Kun Wang, Yang Liu, Tao Wu, Dafang Chen, Yonghua Hu & Yiqun WuDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenXiaoying KangDepartment of Neurology, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, USAXiaoying KangDepartment of Neurology, Peking University People’s Hospital, Beijing, ChinaYao YuFangshan District Center for Disease Control and Prevention, Beijing, ChinaHaiying GongDepartment of Epidemiology and Population Health, Yeshiva University Albert Einstein College of Medicine, Bronx, NY, USATao WangAuthorsKexin DingView author publicationsYou can also search for this author in.

82073642）。作者信息作者注意到这些作者共同监督了这项工作：秦雪英，吴益群。作者和附属机构北京大学公共卫生学院流行病学和生物统计学系；教育部重大疾病流行病学重点实验室（北京大学），北京，丁克欣，秦雪英，王怀荣，王坤，刘洋，吴涛，陈大芳，胡永华，吴益群医学流行病学和生物统计学系，卡罗琳斯卡研究所，斯德哥尔摩，瑞典，康小英，布莱根妇女医院和哈佛医学院神经内科，波士顿，马萨诸塞州，美国康小英北京大学人民医院神经内科，北京，北京，中国姚玉房山区疾病预防控制中心，北京，中国海英爱因斯坦医学院，纽约州布朗克斯，USATao Wang作者Kexin DingView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsYiqun Wu and Xueying Qin designed the study. Kexin Ding undertook data processing and conducted data analysis. Yiqun Wu, Xueying Qin, and Kexin Ding drafted the manuscript. Tao Wang, Huairong Wang, and Kun Wang contributed to the manuscript writing.

PubMed谷歌学术贡献吴一群和秦雪莹设计了这项研究。丁可欣进行了数据处理并进行了数据分析。吴益群，秦雪英和丁克欣起草了手稿。王涛，王怀荣和王坤为稿件撰写做出了贡献。

Xiaoying Kang and Tao Wang provided support for the data analysis. Yao Yu, Yang Liu, Haiying Gong, Tao Wang, Xiaoying Kang, Tao Wu, Dafang Chen, and Yonghua Hu revised the manuscript. Yiqun Wu, Xueying Qin, and Kexin Ding were responsible for interpreting the data that the manuscript is based on. All authors have read and approved the final manuscript.Corresponding authorsCorrespondence to.

康晓颖和王涛为数据分析提供了支持。姚宇，杨柳，龚海英，王涛，康晓英，吴涛，陈大方和胡永华修订了手稿。吴益群，秦雪英和丁可欣负责解释稿件所依据的数据。所有作者都阅读并批准了最终稿件。通讯作者通讯。

Xueying Qin or Yiqun Wu.Ethics declarations

秦雪英或吴益群。道德宣言

Competing interests

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Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editors: Kaoru Ito and Dario Ummarino.

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Reprints and permissionsAbout this articleCite this articleDing, K., Qin, X., Wang, H. et al. Identification of shared genetic etiology of cardiovascular and cerebrovascular diseases through common cardiometabolic risk factors.

转载和许可本文引用本文Ding，K.，Qin，X.，Wang，H。等人。通过常见的心脏代谢危险因素鉴定心脑血管疾病的共同遗传病因。

Commun Biol 7, 1703 (2024). https://doi.org/10.1038/s42003-024-07417-6Download citationReceived: 14 June 2024Accepted: 18 December 2024Published: 27 December 2024DOI: https://doi.org/10.1038/s42003-024-07417-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Commun Biol 71703（2024）。https://doi.org/10.1038/s42003-024-07417-6Download引文接收日期：2024年6月14日接受日期：2024年12月18日发布日期：2024年12月27日OI：https://doi.org/10.1038/s42003-024-07417-6Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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Cardiovascular diseasesRisk factorsStroke

心血管疾病危险因素中风