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

PLoS One. 2021 Apr 29;16(4):e0249997. doi: 10.1371/journal.pone.0249997. eCollection 2021.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / therapeutic use
  • Bradycardia / etiology*
  • Bradycardia / genetics
  • China
  • Female
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Protein Interaction Maps / genetics
  • Schizophrenia / drug therapy
  • Schizophrenia / genetics*
  • Schizophrenia / pathology
  • Tumor Suppressor Protein p53 / metabolism
  • alpha Catenin / genetics

Substances

  • Antipsychotic Agents
  • CTNNA3 protein, human
  • Membrane Proteins
  • SUSD6 protein, human
  • Tumor Suppressor Protein p53
  • alpha Catenin

Grants and funding

This work was supported by Research Fund for Academician Lin He New Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.