Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.
National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China.
Transl Psychiatry. 2022 Feb 8;12(1):56. doi: 10.1038/s41398-022-01825-0.
QTc interval prolongation is one of the most common antipsychotic-induced side effects which could lead to ventricular tachycardia or Torsade de Pointes, even cardiac arrest. There is very limited understanding on the genetic factors that associated with antipsychotic-induced QTc interval change. We conducted a genome-wide association study (GWAS) of antipsychotic-induced QTc interval change among patients with schizophrenia. A total of 2040 patients with schizophrenia were randomly assigned to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and first-generation antipsychotics; first-generation antipsychotics including haloperidol or perphenazine were also assigned randomly) and received 6-week antipsychotic treatment. We identified two novel loci (rs200050752 in ATAD3B and rs186507741 in SKIL) that were associated with antipsychotic-induced QTc interval change at a genome-wide significance level. The combination of polygenic risk score (PRS), based the GWAS of myocardial infarction from BioBank Japan project, and clinical data (sex, heart rate and QTc interval at baseline) could be applied to predict whether patients with schizophrenia have QTc interval prolongation (10 ms was applied as threshold, P < 0.001, area under the curve [AUC] was 0.797), especially for the first episode patients (P < 0.001, AUC was 0.872). We identified two loci located within genes related to mitochondrial function and cell growth and differentiation, which were both associated with schizophrenia and heart function. The combination of PRS and clinical data could predict whether patients with schizophrenia have the side effect of QTc interval prolongation, which could fundamentally guide the choice of antipsychotic in patients with schizophrenia, especially for the first-episode patients.
QTc 间期延长是最常见的抗精神病药物引起的副作用之一，可导致室性心动过速或尖端扭转型室性心动过速，甚至心脏骤停。对抗精神病药物引起的 QTc 间期变化相关的遗传因素的了解非常有限。我们进行了一项精神分裂症患者抗精神病药物引起的 QTc 间期变化的全基因组关联研究（GWAS）。共有 2040 名精神分裂症患者被随机分为六组（奥氮平、利培酮、喹硫平、阿立哌唑、齐拉西酮和第一代抗精神病药；第一代抗精神病药包括氟哌啶醇或奋乃静也被随机分配），并接受 6 周的抗精神病药物治疗。我们发现了两个新的基因座（ATAD3B 中的 rs200050752 和 SKIL 中的 rs186507741），它们与抗精神病药物引起的 QTc 间期变化在全基因组显著水平相关。基于日本生物银行项目的心肌梗死 GWAS 的多基因风险评分（PRS）与临床数据（性别、心率和基线时的 QTc 间期）相结合，可用于预测精神分裂症患者是否存在 QTc 间期延长（以 10ms 为阈值，P<0.001，曲线下面积 [AUC] 为 0.797），尤其是首发患者（P<0.001，AUC 为 0.872）。我们发现了两个位于与线粒体功能和细胞生长分化相关基因内的基因座，它们都与精神分裂症和心脏功能有关。PRS 和临床数据的结合可以预测精神分裂症患者是否存在 QTc 间期延长的副作用，这可以从根本上指导精神分裂症患者抗精神病药物的选择，尤其是首发患者。
