Genetic overlap for ten cardiovascular diseases: A comprehensive gene-centric pleiotropic association analysis and Mendelian randomization study

Zeye Liu; Jing Xu; Jiangshan Tan; Xiaofei Li; Fengwen Zhang; Wenbin Ouyang; Shouzheng Wang; Yuan Huang; Shoujun Li; Xiangbin Pan

doi:10.1016/j.isci.2023.108150

Genetic overlap for ten cardiovascular diseases: A comprehensive gene-centric pleiotropic association analysis and Mendelian randomization study

iScience. 2023 Oct 6;26(11):108150. doi: 10.1016/j.isci.2023.108150. eCollection 2023 Nov 17.

Authors

Zeye Liu^{1

2

3

4}, Jing Xu⁵, Jiangshan Tan⁶, Xiaofei Li⁷, Fengwen Zhang^{1

2

3

4}, Wenbin Ouyang^{1

2

3

4}, Shouzheng Wang^{1

2

3

4}, Yuan Huang⁸, Shoujun Li⁸, Xiangbin Pan^{1

2

3

4}

Affiliations

¹ Department of Structural Heart Disease, National Center for Cardiovascular Disease, China & Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100037, China.
² National Health Commission Key Laboratory of Cardiovascular Regeneration Medicine, Beijing 100037, China.
³ Key Laboratory of Innovative Cardiovascular Devices, Chinese Academy of Medical Sciences, Beijing 100037, China.
⁴ National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing 100037, China.
⁵ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China.
⁶ Key Laboratory of Pulmonary Vascular Medicine, National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
⁷ Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁸ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China.

Abstract

Recent studies suggest that pleiotropic effects may explain the genetic architecture of cardiovascular diseases (CVDs). We conducted a comprehensive gene-centric pleiotropic association analysis for ten CVDs using genome-wide association study (GWAS) summary statistics to identify pleiotropic genes and pathways that may underlie multiple CVDs. We found shared genetic mechanisms underlying the pathophysiology of CVDs, with over two-thirds of the diseases exhibiting common genes and single-nucleotide polymorphisms (SNPs). Significant positive genetic correlations were observed in more than half of paired CVDs. Additionally, we investigated the pleiotropic genes shared between different CVDs, as well as their functional pathways and distribution in different tissues. Moreover, six hub genes, including ALDH2, XPO1, HSPA1L, ESR2, WDR12, and RAB1A, as well as 26 targeted potential drugs, were identified. Our study provides further evidence for the pleiotropic effects of genetic variants on CVDs and highlights the importance of considering pleiotropy in genetic association studies.

Keywords: Association analysis; Cardiovascular medicine; Computational bioinformatics; Human Genetics; Quantitative genetics.