Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients\u2014a genome-wide association study adjusting for smoking habits

Robert Løvsletten Smith,Ole A Andreassen,Srdjan Djurovic,Marianne Kristiansen Kringen,Lavinia Athanasiu,Espen Molden,Kevin O'Connell

doi:10.1038/s41398-020-00888-1

Abstract

Clozapine (CLZ) is the superior antipsychotic drug for treatment of schizophrenia, but exhibits an extensive interpatient pharmacokinetic variability. Here, we conducted a genome-wide association study (GWAS) of CLZ serum concentration adjusting for known smoking habits, which is a major nongenetic factor reducing CLZ levels. The study included 484 patients with 10,283 steady-state serum concentrations of CLZ and N-desmethylclozapine, prescribed dosing, co-medications and known smoking habits (n = 422; 9284 serum samples) from a therapeutic drug monitoring (TDM) service. The GWAS analyses were performed with and without smoking habits as covariate, where possible hits were assessed in relation to the target CLZ concentration range applied in the TDM service (300–2500 nmol/L). The smoking-independent analysis of N-desmethylclozapine serum concentration and the CLZ-to-N-desmethylclozapine ratio replicated the previously identified locus on chromosome 4. After adjusting for smoking habits in patients confirmed as ‘smokers’ (61%) or ‘nonsmokers’ (39%), a novel variant (rs28379954; minor T>C allele frequency 4.1%; 7.6% CT carriers in the population) within the gene encoding the nuclear factor 1 B-type (NFIB) was significantly associated with reduced CLZ serum concentration (p = 1.68 × 10−8, beta = −0.376; explained variance 7.63%). There was no significant association between rs28379954 and N-desmethylclozapine concentration in the GWAS analysis (p = 5.63 × 10−5). The fraction of CLZ TDM samples below 300 nmol/L was significantly higher in carriers vs. noncarriers of the rs28379954 minor C allele [12.0% (95% CI: 9.4–14.7) vs. 6.2% (95% CI: 5.7–6.8), p < 0.001]. We identified a novel variant in the NFIB gene associated with reduced CLZ levels and increased risk of subtherapeutic serum concentrations. This warrants testing of clinical relevance of screening for this gene variant, and also experimental studies to investigate the biological mechanisms of NFIB involvement in CLZ pharmacokinetics.

Highlights

Clozapine (CLZ) is the most efficient antipsychotic drug in treatment of schizophrenia[1]
When adjusting for known smoking habits, which have a major effect on CLZ metabolism[13,14], we identified a novel locus in the NFIB gene associated with a significant reduction in CLZ serum concentrations
According to our findings in the genome-wide association study (GWAS) analysis adjusting for smoking habits, heterozygous carriers of the minor rs28379954 C allele are associated with a substantial decrease in CLZ serum concentration, i.e., an estimated reduction of 37.6% in the dose-adjusted serum concentration of CLZ compared with homozygous carriers of the wild type allele

Summary

Introduction

Clozapine (CLZ) is the most efficient antipsychotic drug in treatment of schizophrenia[1]. In contrast to polygenic complex traits, such as schizophrenia[17], these results support the hypothesis that the genetic architecture of CLZ metabolism is less polygenic and may constitute a smaller number of variants with larger effect sizes[16,18]. This is typical for the pharmacogenetics of drug-metabolizing enzymes, where a limited number of variant allele diplotypes have large effect sizes and separate the population into distinct metabolizer phenotypes[19,20]. CLZ related adverse effects are associated with few genetic variants with large effect sizes[21,22]

Objectives

Methods

Results

Conclusion