Key result
Whole-genome sequencing identified 15 genes nominally associated (p<0.05) with clozapine-induced myocarditis based on rare variant gene-burden analysis, though none survived multiple testing correction.
Why the study?
Clozapine carries a risk of rare but potentially fatal myocarditis, but the contributions of cytochrome P450 DNA variations, copy number variants, and rare deleterious variants have not been investigated.
Case-Control (n=50)
Yes
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Whole-genome sequencing identified 15 novel candidate genes nominally associated with clozapine-induced myocarditis, suggesting a complex polygenic architecture for this adverse drug reaction.
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.
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Narang et al. (2021) conducted a case-control in Clozapine-induced myocarditis in schizophrenia-spectrum disorders (n=50). Rare and deleterious genetic variants vs. Clozapine-tolerant controls was evaluated on Association of rare and deleterious genetic variants with clozapine-induced myocarditis (gene-burden analysis) (p=<0.05). Whole-genome sequencing identified 15 genes nominally associated (p<0.05) with clozapine-induced myocarditis based on rare variant gene-burden analysis, though none survived multiple testing correction.
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