Antonio F Pardiñas1, Mariana Nalmpanti1, Andrew J Pocklington1, Sophie E Legge1, Christopher Medway1, Adrian King1, John Jansen1, Marinka Helthuis1, Stanley Zammit1, James MacCabe1, Michael J Owen1, Michael C O'Donovan1, James T R Walters1. 1. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe).
Abstract
OBJECTIVE: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. METHODS: The authors 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. These analyses were adjusted 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 that might interact with clozapine pharmacokinetics. RESULTS: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (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 of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the 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 patients with treatment-resistant schizophrenia.
OBJECTIVE:Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. METHODS: The authors 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. These analyses were adjusted 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 that might interact with clozapine pharmacokinetics. RESULTS: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (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 of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the 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 patients with treatment-resistant schizophrenia.
Authors: C Okhuijsen-Pfeifer; M Z van der Horst; C A Bousman; B Lin; K R van Eijk; S Ripke; Y Ayhan; M O Babaoglu; M Bak; W Alink; H van Beek; E Beld; A Bouhuis; M Edlinger; I M Erdogan; A Ertuğrul; G Yoca; I P Everall; T Görlitz; K P Grootens; S Gutwinski; T Hallikainen; E Jeger-Land; M de Koning; M Lähteenvuo; S E Legge; S Leucht; C Morgenroth; A Müderrisoğlu; A Narang; C Pantelis; A F Pardiñas; T Oviedo-Salcedo; J Schneider-Thoma; S Schreiter; E Repo-Tiihonen; H Tuppurainen; M Veereschild; S Veerman; M de Vos; E Wagner; D Cohen; J P A M Bogers; J T R Walters; A E Anil Yağcıoğlu; J Tiihonen; A Hasan; J J Luykx Journal: Transl Psychiatry Date: 2022-04-07 Impact factor: 7.989
Authors: Isabella R Willcocks; Sophie E Legge; Mariana Nalmpanti; Lucy Mazzeo; Adrian King; John Jansen; Marinka Helthuis; Michael J Owen; Michael C O'Donovan; James T R Walters; Antonio F Pardiñas Journal: Front Pharmacol Date: 2021-04-16 Impact factor: 5.810
Authors: Roos van Westrhenen; Katherine J Aitchison; Magnus Ingelman-Sundberg; Marin M Jukić Journal: Front Psychiatry Date: 2020-03-12 Impact factor: 4.157