Whole-genome sequencing analysis of clozapine-induced myocarditis

Pharmacogenomics J. 2022 May;22(3):173-179. doi: 10.1038/s41397-022-00271-x. Epub 2022 Apr 23.

Abstract

One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents* / adverse effects
  • Clozapine* / adverse effects
  • Genome-Wide Association Study
  • Humans
  • Myocarditis* / chemically induced
  • Myocarditis* / drug therapy
  • Myocarditis* / genetics
  • Schizophrenia* / drug therapy
  • Schizophrenia* / genetics

Substances

  • Antipsychotic Agents
  • Clozapine