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.

限制在精神分裂症治疗中使用氯氮平的担忧之一是存在罕见但可能致命的心肌炎的风险。我们之前的全基因组关联研究和人类白细胞抗原分析确定了与氯氮平诱导的心肌炎相关的假定基因座。然而，尚未研究 DNA 变异在细胞色素 P450 基因、拷贝数变异和罕见的有害变异中的贡献。我们使用来自 25 例氯氮平诱发的心肌炎病例和 25 名人口统计学匹配的耐氯氮平对照受试者的全基因组测序数据探索了这些未探索的 DNA 变异类别。我们根据罕见变异基因负载分析确定了 15 个基因（MLLT6、CADPS、TACC2、L3MBTL4、NPY、SLC25A21、PARVB、GPR179、ACAD9、NOL8、C5orf33、FAM127A、AFDN、SLC6A11、PXDN）名义上 与氯氮平诱发的心肌炎相关（ p < 0.05）。在这些基因中，13 个在人心肌组织中表达。尽管需要独立复制这些发现，但我们的研究提供了关于罕见遗传变异在氯氮平诱导的心肌炎易感性中的潜在作用的初步见解。