Skip to content
DraconiticResearch
Search Sources API
197,578 studies31 sourcesUpdated 28 min ago
Peer-reviewedCC BY-NC-NDJournal of the American Heart Association

Multivariate Genomic Analysis Reveals Shared Genetic Architecture and Potential Therapeutic Targets for Atherosclerotic Cardiovascular Disease

  • Yifeng Xu1
  • Jie Wang1
  • Ruoqi Zhang1
  • Chengzhi Hou1
  • Xuan Sun1
  • Qiyang Li2
  • Chao Liu1
  1. 1China Academy of Chinese Medical Sciences
  2. 2Hubei University of Chinese Medicine
Open at sourceDOICite

Abstract

Background Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality worldwide and comprises multiple clinical phenotypes, but their shared genetic architecture remains incompletely defined. Methods We integrated genome‐wide association study summary statistics for coronary artery disease, peripheral artery disease, large‐artery atherosclerotic stroke, and carotid plaque using genomic structural equation modeling to derive a multivariable ASCVD common factor. We applied fine‐mapping, multi‐marker analysis of genomic annotation, transcriptome‐wide association studies, Mendelian randomization, colocalization, mediation analysis, and virtual screening. Results We identified 289 linkage disequilibrium–independent lead single‐nucleotide polymorphisms mapping to 177 genomic risk loci; 13 lacked corresponding genome‐wide significant signals in the input genome‐wide association studies. Eleven had prior genome‐wide association study catalog association records, whereas no relevant records were identified for the loci represented by rs2294777 near SASH1 and rs4843053 near AKAP13 . Fine‐mapping prioritized 26 putative causal variants. Integrated functional summary‐based imputation, multi‐tissue transcriptome‐wide association study, and multi‐marker analysis of genomic annotation analyses implicated 123 genes. Enrichment analyses highlighted endothelial cells and H3K27ac‐marked regulatory regions. Lipidomic analyses linked higher triacylglycerols and sterol esters to increased multivariable ASCVD common factor risk. Protein Mendelian randomization analyses in deCODE and Fenland prioritized aldehyde dehydrogenase 2 (ALDH2), phosphodiesterase 5A (PDE5A), HtrAserinepeptidase 1 (HTRA1), and transcription elongation factor A2 (TCEA2) as candidate targets. Colocalization supported a shared causal variant between TCEA2 and multivariable ASCVD common factor. Mediation analyses suggested partial mediation by diastolic blood pressure for ALDH2, PDE5A, and TCEA2 and by triglycerides for TCEA2. Virtual screening identified candidate compounds with favorable predicted binding to PDE5A and ALDH2. Conclusions Integrating multivariate genome‐wide association study with multi‐omics and causal inference analyses identified shared genetic signals associated with ASCVD susceptibility and prioritized candidate protein targets, informing future functional studies and target validation.

Related

  1. Protective effects of icariin in atherosclerotic cardiovascular disease: mechanistic basis, post-ischemic protection and translational limitations
    Xuefei Wang, Zongliang Yu, Xiaoya Li +6
    Pharmaceutical biologyPeer-reviewedCC BYFull textPlant biologyEurope PMC
  2. 2D U-NET Deep Learning Architecture for Atherosclerotic Lesion Segmentation and Quantification
    W. Giles, Z. Venetianer, N. Patel +5
    bioRxivPreprintAll rights reservedFull textBioinformatics & computational biologybioRxiv
  3. Revisiting the genetic support of leukotriene pathway drug targets in atherosclerotic cardiovascular disease.
    Tristan St-Laurent, Julien St-Pierre, Julien Quang Le Van +1
    Frontiers in geneticsPeer-reviewedCC BYFull textGenetics & genomicsEurope PMCPMC
  4. Impaired CD4+ T cell response to apolipoprotein B-100 peptide P210 in atherosclerotic cardiovascular disease is reversed by P210-conjugated nanoparticles
    Paul C. Dimayuga, Jianchang Zhou, Xiaoning Zhao +7
    American journal of physiology. Heart and circulatory physiologyPeer-reviewedCC BY 4.0Full text1 citedImmunologyPMC
  5. Identification and validation of cholesterol homeostasis and NK cell-associated predictive and therapeutic models for Coronary atherosclerotic heart disease patients with ST-elevated myocardial infarction: Insights from artificial intelligence and multi-omics
    Xuemei Chen, Yifan Zhao, Xixi Guo +5
    Computational Biology and ChemistryPeer-reviewedCC BY-NC-ND7 citedImmunologyOpenAlex

Cite

BibTeXRIS
BibTeX
@article{xu2026multivariate,
  title = {{Multivariate Genomic Analysis Reveals Shared Genetic Architecture and Potential Therapeutic Targets for Atherosclerotic Cardiovascular Disease}},
  author = {Yifeng Xu and Jie Wang and Ruoqi Zhang and Chengzhi Hou and Xuan Sun and Qiyang Li and Chao Liu},
  journal = {Journal of the American Heart Association},
  year = {2026},
  month = oct,
  doi = {10.1161/jaha.126.050689},
  url = {https://www.ahajournals.org/doi/10.1161/JAHA.126.050689},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Multivariate Genomic Analysis Reveals Shared Genetic Architecture and Potential Therapeutic Targets for Atherosclerotic Cardiovascular Disease
AU  - Yifeng Xu
AU  - Jie Wang
AU  - Ruoqi Zhang
AU  - Chengzhi Hou
AU  - Xuan Sun
AU  - Qiyang Li
AU  - Chao Liu
PY  - 2026
DA  - 2026/10/20
JO  - Journal of the American Heart Association
DO  - 10.1161/jaha.126.050689
UR  - https://www.ahajournals.org/doi/10.1161/JAHA.126.050689
AB  - Background Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality worldwide and comprises multiple clinical phenotypes, but their shared genetic architecture remains incompletely defined. Methods We integrated genome‐wide association study summary statistics for coronary artery disease, peripheral artery disease, large‐artery atherosclerotic stroke, and carotid plaque using genomic structural equation modeling to derive a multivariable ASCVD common factor. We applied fine‐mapping, multi‐marker analysis of genomic annotation, transcriptome‐wide association studies, Mendelian randomization, colocalization, mediation analysis, and virtual screening. Results We identified 289 linkage disequilibrium–independent lead single‐nucleotide polymorphisms mapping to 177 genomic risk loci; 13 lacked corresponding genome‐wide significant signals in the input genome‐wide association studies. Eleven had prior genome‐wide association study catalog association records, whereas no relevant records were identified for the loci represented by rs2294777 near SASH1 and rs4843053 near AKAP13 . Fine‐mapping prioritized 26 putative causal variants. Integrated functional summary‐based imputation, multi‐tissue transcriptome‐wide association study, and multi‐marker analysis of genomic annotation analyses implicated 123 genes. Enrichment analyses highlighted endothelial cells and H3K27ac‐marked regulatory regions. Lipidomic analyses linked higher triacylglycerols and sterol esters to increased multivariable ASCVD common factor risk. Protein Mendelian randomization analyses in deCODE and Fenland prioritized aldehyde dehydrogenase 2 (ALDH2), phosphodiesterase 5A (PDE5A), HtrAserinepeptidase 1 (HTRA1), and transcription elongation factor A2 (TCEA2) as candidate targets. Colocalization supported a shared causal variant between TCEA2 and multivariable ASCVD common factor. Mediation analyses suggested partial mediation by diastolic blood pressure for ALDH2, PDE5A, and TCEA2 and by triglycerides for TCEA2. Virtual screening identified candidate compounds with favorable predicted binding to PDE5A and ALDH2. Conclusions Integrating multivariate genome‐wide association study with multi‐omics and causal inference analyses identified shared genetic signals associated with ASCVD susceptibility and prioritized candidate protein targets, informing future functional studies and target validation.
SN  - 2047-9980
ER  -