Zhong Peng, Zhang Chumeng, Wu Qinfeng, Chang Xiao
Department of Cardiology, Jining No.1 People's Hospital, Jining, Shandong, China.
The Second School of Clinical Medicine of Shandong First Medical University, Tai'an, Shandong, China.
Front Genet. 2025 Jun 24;16:1635378. doi: 10.3389/fgene.2025.1635378. eCollection 2025.
Cardiovascular diseases (CVDs), including myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and arrhythmia, are major contributors to global mortality and often share overlapping risk factors and pathophysiological mechanisms. While genome-wide association studies (GWAS) have identified many loci for individual CVDs, the shared genetic architecture across related traits-particularly in East Asian populations-remains underexplored.
We integrated large-scale GWAS summary statistics from East Asian populations to perform genome-wide and local genetic correlation analyses across four CVD phenotypes and five cardiometabolic traits (blood pressure and lipid levels). Using stratified LD score regression, we assessed tissue-specific heritability enrichment. Multi-trait analysis of GWAS (MTAG) was then employed to identify pleiotropic loci associated with multiple traits, with functional annotation and expression quantitative trait loci (eQTL) data used to explore biological relevance.
We observed extensive genetic correlations among CVDs and between CVDs and cardiometabolic traits, with HF showing the strongest connections to both MI and arrhythmia. Notable genome-wide correlations were found between MI and SBP (rg = 0.35, = 1.59 × 10) and between HF and DBP (rg = 0.54, = 9.84 × 10). Stratified heritability analyses revealed significant enrichment in heart and arterial tissues, highlighting the relevance of cardiovascular-specific regulatory elements. MTAG identified several pleiotropic loci, including established genes such as and , and novel East Asian-enriched signals such as and /. Functional data indicated that variants regulate gene expression in arterial and cardiac tissues, implicating redox regulation in HF and hypertension pathogenesis.
Our findings provide comprehensive insight into the shared genetic determinants of cardiovascular and metabolic diseases in East Asian populations. The identification of pleiotropic and ancestry-specific loci, along with tissue-specific regulatory patterns, underscores the need for integrative multi-trait and population-informed approaches in cardiovascular genetics and risk prediction.
心血管疾病（CVDs），包括心肌梗死（MI）、心力衰竭（HF）、心房颤动（AF）和心律失常，是全球死亡率的主要贡献因素，并且常常具有重叠的风险因素和病理生理机制。虽然全基因组关联研究（GWAS）已经确定了许多个体心血管疾病的基因座，但相关性状之间共享的遗传结构——特别是在东亚人群中——仍未得到充分探索。
我们整合了来自东亚人群的大规模GWAS汇总统计数据，以对四种心血管疾病表型和五种心脏代谢性状（血压和血脂水平）进行全基因组和局部遗传相关性分析。使用分层LD评分回归，我们评估了组织特异性遗传力富集情况。然后采用GWAS多性状分析（MTAG）来识别与多种性状相关的多效性基因座，并使用功能注释和表达定量性状基因座（eQTL）数据来探索生物学相关性。
我们观察到心血管疾病之间以及心血管疾病与心脏代谢性状之间存在广泛的遗传相关性，其中HF与MI和心律失常的联系最为紧密。在MI和收缩压（SBP）之间（rg = 0.35， = 1.59 × 10）以及HF和舒张压（DBP）之间（rg = 0.54， = 9.84 × 10）发现了显著的全基因组相关性。分层遗传力分析显示心脏和动脉组织中有显著富集，突出了心血管特异性调控元件的相关性。MTAG识别出了几个多效性基因座，包括已确定的基因如 和 ，以及新的东亚富集信号如 和 / 。功能数据表明 变体调节动脉和心脏组织中的基因表达，这意味着氧化还原调节在HF和高血压发病机制中起作用。
我们的研究结果为东亚人群心血管和代谢疾病的共享遗传决定因素提供了全面的见解。多效性和祖先特异性基因座的识别，以及组织特异性调控模式，强调了在心血管遗传学和风险预测中采用综合多性状和人群知情方法的必要性。
