Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Chromosome Laboratory, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Int J Legal Med. 2021 Jul;135(4):1395-1405. doi: 10.1007/s00414-021-02595-y. Epub 2021 May 11.
Cardiac diseases and sudden cardiac death (SCD) are more prevalent in individuals diagnosed with schizophrenia compared to the general population, with especially coronary artery disease (CAD) as the major cardiovascular cause of death. Antipsychotic medications, genetics, and lifestyle factors may contribute to the increased SCD in individuals with schizophrenia. The role of antipsychotic medications and lifestyle factors have been widely investigated, while the genetic predisposition to inherited cardiac diseases in schizophrenia is poorly understood. In this study, we examined 100 genes associated with inherited cardiomyopathies and cardiac channelopathies in 97 deceased individuals diagnosed with schizophrenia for the prevalence of genetic variants associated with SCD. The deceased individuals had various causes of death and were included in the SURVIVE project, a prospective, autopsy-based study of mentally ill individuals in Denmark. This is the first study of multiple inherited cardiac disease-related genes in deceased individuals with diagnosed schizophrenia to shed light on the genetic predisposition to SCD in individuals with schizophrenia. We found no evidence for an overrepresentation of rare variants with high penetrance in inherited cardiac diseases, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG) consensus guidelines. However, we found that the deceased individuals had a statistically significantly increased polygenic burden caused by variants in the investigated heart genes compared to the general population. This indicates that common variants with smaller effects in heart genes may play a role in schizophrenia.
心脏病和心源性猝死（SCD）在被诊断为精神分裂症的个体中比一般人群更为普遍，其中冠状动脉疾病（CAD）是主要的心血管死亡原因。抗精神病药物、遗传和生活方式因素可能导致精神分裂症患者 SCD 风险增加。抗精神病药物和生活方式因素的作用已经得到广泛研究，而精神分裂症中与遗传性心脏病相关的遗传易感性则知之甚少。在这项研究中，我们检查了 97 名已故精神分裂症患者中与遗传性心肌病和心脏通道病相关的 100 个基因，以确定与 SCD 相关的遗传变异的流行率。这些已故个体的死因各不相同，并且被纳入了 SURVIVE 项目，这是一项在丹麦对精神病患者进行前瞻性、基于尸检的研究。这是首例对患有诊断性精神分裂症的已故个体进行的多个遗传性心脏疾病相关基因研究，旨在揭示精神分裂症患者 SCD 的遗传易感性。根据美国医学遗传学和基因组学学院以及分子病理学协会（ACMG）的共识指南，我们没有发现遗传性心脏疾病中高外显率罕见变异过度代表的证据。然而，我们发现与一般人群相比，研究中的心脏基因中的变异导致已故个体的多基因负担统计学上显著增加。这表明心脏基因中常见的、效应较小的变异可能在精神分裂症中发挥作用。
