Treur Jorien L, Thijssen Anaïs B, Smit Dirk J A, Tadros Rafik, Veeneman Rada R, Denys Damiaan, Vermeulen Jentien M, Barc Julien, Bergstedt Jacob, Pasman Joëlle A, Bezzina Connie R, Verweij Karin J H
Genetic Epidemiology, Department of Psychiatry, Amsterdam UMC, University of Amsterdam, The Netherlands.
Cardiovascular Genetics Center, Montréal Heart Institute, Faculty of Medicine, Montréal, Canada.
Br J Psychiatry. 2025 Mar;226(3):153-161. doi: 10.1192/bjp.2024.165. Epub 2024 Nov 8.
An important contributor to the decreased life expectancy of individuals with schizophrenia is sudden cardiac death. Arrhythmic disorders may play an important role herein, but the nature of the relationship between schizophrenia and arrhythmia is unclear.
To assess shared genetic liability and potential causal effects between schizophrenia and arrhythmic disorders and electrocardiogram (ECG) traits.
We leveraged summary-level data of large-scale genome-wide association studies of schizophrenia (53 386 cases, 77 258 controls), arrhythmic disorders (atrial fibrillation, 55 114 cases, 482 295 controls; Brugada syndrome, 2820 cases, 10 001 controls) and ECG traits (heart rate (variability), PR interval, QT interval, JT interval and QRS duration, = 46 952-293 051). We examined shared genetic liability by assessing global and local genetic correlations and conducting functional annotation. Bidirectional causal relations between schizophrenia and arrhythmic disorders and ECG traits were explored using Mendelian randomisation.
There was no evidence for global genetic correlation, except between schizophrenia and Brugada syndrome ( = 0.14, 95% CIs = 0.06-0.22, = 4.0E-04). In contrast, strong positive and negative local correlations between schizophrenia and all cardiac traits were found across the genome. In the most strongly associated regions, genes related to immune and viral response mechanisms were overrepresented. Mendelian randomisation indicated that liability to schizophrenia causally increases Brugada syndrome risk (beta = 0.14, CIs = 0.03-0.25, = 0.009) and heart rate during activity (beta = 0.25, CIs = 0.05-0.45, = 0.015).
Despite little evidence for global genetic correlation, specific genomic regions and biological pathways emerged that are important for both schizophrenia and arrhythmia. The putative causal effect of liability to schizophrenia on Brugada syndrome warrants increased cardiac monitoring and early medical intervention in people with schizophrenia.
精神分裂症患者预期寿命降低的一个重要因素是心源性猝死。心律失常紊乱可能在此过程中起重要作用，但精神分裂症与心律失常之间关系的本质尚不清楚。
评估精神分裂症与心律失常紊乱及心电图（ECG）特征之间的共同遗传易感性和潜在因果效应。
我们利用了精神分裂症（53386例患者，77258例对照）、心律失常紊乱（心房颤动，55114例患者，482295例对照；布加综合征，2820例患者，10001例对照）和ECG特征（心率（变异性）、PR间期、QT间期、JT间期和QRS时限，n = 46952 - 293051）的大规模全基因组关联研究的汇总数据。我们通过评估全局和局部遗传相关性并进行功能注释来检查共同遗传易感性。使用孟德尔随机化探索精神分裂症与心律失常紊乱及ECG特征之间的双向因果关系。
除精神分裂症与布加综合征之间外（r = 0.14，95%CI = 0.06 - 0.22，P = 4.0E - 04），没有证据表明存在全局遗传相关性。相比之下，在全基因组中发现精神分裂症与所有心脏特征之间存在强的正、负局部相关性。在关联最强的区域，与免疫和病毒反应机制相关的基因过度富集。孟德尔随机化表明，精神分裂症易感性因果性增加布加综合征风险（β = 0.14，CI = 0.03 - 0.25，P = 0.009）以及活动期间的心率（β = 0.25，CI = 0.05 - 0.45，P = 0.015）。
尽管几乎没有证据表明存在全局遗传相关性，但出现了对精神分裂症和心律失常均重要的特定基因组区域和生物学途径。精神分裂症易感性对布加综合征的假定因果效应值得对精神分裂症患者加强心脏监测和早期医学干预。
