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Whole-genome sequencing analysis of clozapine-induced myocarditis

The Pharmacogenomics Journal volume 22, pages 173–179 (2022)Cite this article

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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.

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Fig. 1: PROCLAIM study design, analysis and key results.
Fig. 2: Distribution of titration slopes by history of clozapine-induced myocarditis.
Fig. 3: Normalised RNASeq read counts of the 15 nominally associated loci identified in gene burden analysis in left ventricular septal tissue of healthy adult donors (n = 21).

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Acknowledgements

The work was supported in part by the University of Calgary Cumming School of Medicine, Alberta Children’s Hospital Research Institute, and University of Melbourne Establishment Grant. P.L is supported by a National Heart Foundation Future Leader Fellowship (102604). JMCN is supported by an NHMRC Leadership award (IG1173690). CP was supported by a National Health and Medical Research Council (NHMRC) L3 Investigator Grant (1196508) and NHMRC Program Grant (ID: 566529). Access to high performance computing was provided by The Centre for Health Genomics and Informatics (CHGI) at University of Calgary.

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Authors and Affiliations

  1. Department of Medical Genetics, University of Calgary, Calgary, AB, Canada

    Ankita Narang & Chad A. Bousman

  2. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia

    Paul Lacaze, Kathlyn J. Ronaldson & John J. McNeil

  3. Adult Mental Health Rehabilitation Unit, North Western Mental Health, Melbourne Health, Western Health, Sunshine Hospital, St Albans, VIC, Australia

    Mahesh Jayaram, Naveen Thomas & Christos Pantelis

  4. Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Western Centre for Health & Education, St Albans, VIC, Australia

    Mahesh Jayaram, Naveen Thomas & Christos Pantelis

  5. Department of Psychiatry, University of Calgary, Calgary, AB, Canada

    Rory Sellmer, David N. Crockford & Chad A. Bousman

  6. Departments of Psychiatry and Neurology (Medicine), Neuropsychiatry Program, and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada

    Robert Stowe

  7. Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  8. Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  9. Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway & Chad A. Bousman

  10. Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  11. Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Steven C. Greenway

  12. Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

  13. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Chad A. Bousman

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  1. Ankita Narang
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Contributions

CB and CP conceptualized the study. AN and CB conducted the analyses and wrote the first draft of the manuscript. PL, KR, JM, MJ, NT, RS, DC, RS, SG, and CP contributed to subsequent drafts of the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Chad A. Bousman.

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Competing interests

CAB is the founder and a shareholder of Sequence2Script Inc and a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Pharmacogene Variation Consortium (PharmVar). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Narang, A., Lacaze, P., Ronaldson, K.J. et al. Whole-genome sequencing analysis of clozapine-induced myocarditis. Pharmacogenomics J 22, 173–179 (2022). https://doi.org/10.1038/s41397-022-00271-x

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