A Genomic Convergence: Mapping Shared Causal Loci Between Heart Failure and Arrhythmias.

IF 1.7 4区医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiology Pub Date : 2026-03-18 DOI:10.1159/000551373

Zhiheng Xia, Zian Feng, Ang Li, Hao Su

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引用次数: 0

Abstract

Background: Heart failure (HF) and various arrhythmias frequently co-occur in clinical practice, suggesting shared pathophysiological mechanisms. However, the extent and nature of their common genetic architecture remains incompletely understood. This study aimed to systematically investigate the genetic correlations and shared causal loci between HF-related traits and multiple arrhythmia phenotypes.

Methods: We utilized GWAS summary statistics from European cohorts to analyze HF-related traits and ten common arrhythmias. Global genetic correlations were assessed using LDSC and HDL. Local genetic correlations were further investigated using LAVA, HESS, and SUPERGNOVA to identify regional overlaps. Pleiotropic loci were identified using PLACO, with Bayesian colocalization analysis (stringent threshold PP.H4 ≥ 0.75) to assess shared causality. Bidirectional Mendelian randomization (MR) was conducted to explore causal relationships, utilizing a discovery threshold (P < 5×10⁻⁶) and a validation threshold (P < 5×10⁻⁸) with independent FinnGen data.

Results: Significant genome-wide genetic correlations were identified between HF and seven arrhythmia traits, with the strongest association for atrial fibrillation (LDSC rg = 0.42, P = 5.1×10⁻¹⁸; HDL rg = 0.63, P = 5.9×10⁻³⁷). Local genetic correlation analyses identified multiple genomic regions of significant overlap, particularly converging on a major hotspot at the 4q25/PITX2/ENPEP locus across all three methods. Pleiotropic analysis identified several high-confidence shared loci, including regions harboring BAG3 (PP.H4 = 0.990) and ZFHX3 (PP.H4 = 0.938). Bidirectional MR revealed significant causal effects of AF on HF development (IVW OR = 1.22, P = 4.83×10⁻¹⁸) and HF on reduced heart rate variability (P = 1.86×10⁻⁴), both validated in independent cohorts.

Conclusions: Our findings demonstrate substantial and complex shared genetic architecture between HF and multiple arrhythmia phenotypes. These insights identify specific pleiotropic genes, regional correlation hotspots, and causal pathways, potentially informing future precision medicine approaches for cardiovascular disease prevention and treatment.

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基因组趋同：绘制心力衰竭和心律失常之间的共同因果位点。

背景：心力衰竭和各种心律失常在临床中经常同时发生，提示有共同的病理生理机制。然而，他们共同的遗传结构的范围和性质仍然不完全了解。本研究旨在系统探讨hf相关性状与多种心律失常表型之间的遗传相关性和共同因果位点。方法：我们利用来自欧洲队列的GWAS汇总统计分析hf相关特征和10种常见心律失常。使用LDSC和HDL评估全局遗传相关性。利用LAVA、HESS和SUPERGNOVA进一步研究了局部遗传相关性，以确定区域重叠。使用PLACO识别多效位点，并使用贝叶斯共定位分析（严格阈值PP.H4≥0.75）评估共同因果关系。双向孟德尔随机化（MR）利用独立的FinnGen数据，利用发现阈值（P < 5×10⁻⁸）和验证阈值（P < 5×10⁻⁸）来探索因果关系。结果：HF与7种心律失常特征之间存在显著的全基因组遗传相关性，其中与房颤的相关性最强（LDSC rg = 0.42, P = 5.1×10⁻³⁸；HDL rg = 0.63, P = 5.9×10⁻³⁷）。局部遗传相关分析发现，三种方法中存在多个显著重叠的基因组区域，特别是在4q25/PITX2/ENPEP位点的一个主要热点上。多效性分析发现了几个高置信度的共享位点，包括包含BAG3 （PP.H4 = 0.990）和ZFHX3 （PP.H4 = 0.938）的区域。双向磁共振显示心房颤动对HF发展有显著的因果影响（IVW OR = 1.22, P = 4.83×10⁻¹⁸），而心房颤动对心率变异性降低有显著的因果影响（P = 1.86×10⁻⁴），两者都在独立的队列中得到验证。结论：我们的研究结果表明，心衰和多种心律失常表型之间存在大量复杂的共享遗传结构。这些见解确定了特定的多效性基因、区域相关热点和因果途径，可能为未来心血管疾病预防和治疗的精准医学方法提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cardiology 医学-心血管系统

CiteScore

3.40

自引率

5.30%

发文量

审稿时长

1.5 months

期刊介绍： ''Cardiology'' features first reports on original clinical, preclinical and fundamental research as well as ''Novel Insights from Clinical Experience'' and topical comprehensive reviews in selected areas of cardiovascular disease. ''Editorial Comments'' provide a critical but positive evaluation of a recent article. Papers not only describe but offer critical appraisals of new developments in non-invasive and invasive diagnostic methods and in pharmacologic, nutritional and mechanical/surgical therapies. Readers are thus kept informed of current strategies in the prevention, recognition and treatment of heart disease. Special sections in a variety of subspecialty areas reinforce the journal''s value as a complete record of recent progress for all cardiologists, internists, cardiac surgeons, clinical physiologists, pharmacologists and professionals in other areas of medicine interested in current activity in cardiovascular diseases.