Fuzhou Neuro-Psychiatric Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian Province, China.
Shenzhen Baoan Women's and Children's Hospital, Jinan University, Shenzhen, Guangdong Province, China.
PLoS One. 2021 Apr 29;16(4):e0249997. doi: 10.1371/journal.pone.0249997. eCollection 2021.
Second-generation antipsychotics (SGAs) play a critical role in current treatment of schizophrenia (SCZ). It has been observed that sinus bradycardia, rare but in certain situations life threatening adverse drug reaction, can be induced by SGAs across different schizophrenia populations. However, the roles of genetic factors in this phenomenon have not been studied yet. In the present study, a genome-wide association study of single nucleotide polymorphisms (SNPs) was performed on Chinese Han SCZ patients to identify susceptibility loci that were associated with sinus bradycardia induced by SGAs. This study applied microarray to obtain genotype profiles of 88 Han Chinese SCZ patients. Our results found that there were no SNPs had genome-wide significant association with sinus bradycardia induced by SGAs. The top GWAS hit located in gene KIAA0247, which mainly regulated by the tumor suppressor P53 and thus plays a role in carcinogenesis based on resent research and it should not be a susceptibility locus to sinus bradycardia induced by SGAs. Using gene-set functional analysis, we tested that if top 500 SNPs mapped genes were relevant to sinus bradycardia. The result of gene prioritization analysis showed CTNNA3 was strongly correlated with sinus bradycardia, hinting it was a susceptibility gene of this ADR. Our study provides a preliminary study of genetic variants associated with sinus bradycardia induced by SGAs in Han Chinese SCZ patients. The discovery of a possible susceptibility gene shed light on further study of this adverse drug reaction in Han Chinese SCZ patients.
第二代抗精神病药物（SGAs）在当前治疗精神分裂症（SCZ）中发挥着关键作用。据观察，窦性心动过缓是一种罕见但在某些情况下危及生命的药物不良反应，可由不同 SCZ 人群中的 SGAs 引起。然而，遗传因素在这种现象中的作用尚未得到研究。在本研究中，对中国汉族 SCZ 患者进行了单核苷酸多态性（SNP）的全基因组关联研究，以确定与 SGAs 引起的窦性心动过缓相关的易感基因座。本研究应用微阵列技术获得了 88 名汉族 SCZ 患者的基因分型谱。我们的研究结果发现，没有 SNP 与 SGAs 引起的窦性心动过缓具有全基因组显著关联。GWAS 分析的最高关联点位于基因 KIAA0247 中，该基因主要受肿瘤抑制因子 P53 调控，因此根据目前的研究，它在致癌作用中发挥作用，不应是 SGAs 引起窦性心动过缓的易感基因座。使用基因集功能分析，我们测试了 top 500 SNP 映射基因是否与窦性心动过缓相关。基因优先级分析的结果显示 CTNNA3 与窦性心动过缓密切相关，提示其是该药物不良反应的易感基因。本研究初步探讨了汉族 SCZ 患者中与 SGAs 引起的窦性心动过缓相关的遗传变异。易感基因的发现为进一步研究汉族 SCZ 患者的这种药物不良反应提供了线索。
