Genome-wide association study of antipsychotic-induced sinus bradycardia in Chinese schizophrenia patients

Saizheng Weng,Bo Wang,Shan Chao,Rongyan Zheng,Xianhao Lin,Mo Li,Ruiqian Lin,Shaonan Guo,Yinliang Yu,Yun Li

doi:10.1371/journal.pone.0249997

Abstract

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.

Highlights

Schizophrenia (SCZ) is a complex and highly heritable psychiatric disorder with a relatively high prevalence of nearly 7.2/1,000 for lifetime morbid risk [1, 2]
The second-generation antipsychotics (SGAs) have adverse drug reactions (ADRs) on the central nervous system, metabolic system, endocrine system and cardiovascular system [33, 34], and the occurrence of these ADRs is partly owed to hereditary factor
Sinus bradycardia is a rare ADR induced by Second-generation antipsychotics (SGAs), and a thorough understanding of the underlying hereditary factor is not available for this phenomenon

Summary

Introduction

Schizophrenia (SCZ) is a complex and highly heritable psychiatric disorder with a relatively high prevalence of nearly 7.2/1,000 for lifetime morbid risk [1, 2]. SCZ is characterized by emotional dysregulation, positive and negative symptoms, psychosis and cognitive impairment. Several treatments for SCZ exist, but SCZ is difficult to cure completely and high recurrence and disability rates have been noted among SCZ patients. This disease has a considerable adverse influence on work, life and study of patients. Previous studies have shown that multiple factors are involved in the pathogenesis of SCZ, including hereditary factors, environmental factors and other neurological changes in brain [5, 6], the exact pathophysiological mechanisms of SCZ still remain unclear

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