Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism

Antonio F Pardiñas, Mariana Nalmpanti, Andrew Pocklington, Sophie Legge, Christopher Medway, Adrian King, John Jansen, Marinka Helthuis, Stan Zammit, James H MacCabe, Michael J Owen, Michael C O'Donovan, James T Walters

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Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia (TRS), but its worldwide use is still very limited due to its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism might improve clinical management, no robust findings have yet been reported. Our study is the first to adopt the framework of genome-wide association studies to discover genetic markers of clozapine plasma concentrations in a large sample of TRS patients.

Method: We used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service, and carried out a genome-wide analysis of clozapine, norclozapine and their ratio on 10,353 assays from 2,989 individuals. We adjusted these analyses for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways, and compounds which might interact with clozapine pharmacokinetics.

Results: We identify four distinct genome-wide significant loci, which harbour common variants impacting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes, and corroborative evidence for interactions between the metabolism of clozapine, coffee and tobacco. Individual effect of single SNPs fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease in clozapine dose of 50 mg/day. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in our plasma concentration data.

Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of TRS patients.
Original languageEnglish
Pages (from-to)477-486
Number of pages10
JournalAmerican Journal of Psychiatry
Issue number6
Early online date29 Mar 2019
Publication statusPublished - 1 Jun 2019

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    NIHR BRC Mental Health

    Gunnell, D. J.


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    Cite this

    Pardiñas, A. F., Nalmpanti, M., Pocklington, A., Legge, S., Medway, C., King, A., Jansen, J., Helthuis, M., Zammit, S., MacCabe, J. H., Owen, M. J., O'Donovan, M. C., & Walters, J. T. (2019). Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism. American Journal of Psychiatry, 176(6), 477-486.