TY - JOUR
T1 - Whole-genome sequencing analysis of clozapine-induced myocarditis
AU - Narang, Ankita
AU - Lacaze, Paul
AU - Ronaldson, Kathlyn J.
AU - McNeil, John J.
AU - Jayaram, Mahesh
AU - Thomas, Naveen
AU - Sellmer, Rory
AU - Crockford, David N.
AU - Stowe, Robert
AU - Greenway, Steven C.
AU - Pantelis, Christos
AU - Bousman, Chad A.
N1 - Funding Information:
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.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128780594&partnerID=8YFLogxK
U2 - 10.1038/s41397-022-00271-x
DO - 10.1038/s41397-022-00271-x
M3 - Article
C2 - 35461379
AN - SCOPUS:85128780594
SN - 1470-269X
VL - 22
SP - 173
EP - 179
JO - The Pharmacogenomics Journal
JF - The Pharmacogenomics Journal
IS - 3
ER -