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.