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.

氯氮平（CLZ）是用于治疗精神分裂症的高级抗精神病药，但在患者之间具有广泛的药代动力学变异性。在这里，我们进行了针对已知吸烟习惯的CLZ血清浓度调整的全基因组关联研究（GWAS），这是降低CLZ水平的主要非遗传因素。该研究纳入484例患者的CLZ和N-去甲基氯氮平的稳态血药浓度为10,283 ，处方剂量，联合用药和已知吸烟习惯（n = 422; 9284血清样品）来自治疗药物监测（TDM）服务。在有和没有吸烟习惯作为协变量的情况下进行了GWAS分析，其中评估了与TDM服务中应用的目标CLZ浓度范围（300–2500 nmol / L）有关的可能击中次数。对N-去甲基氯氮平血清浓度和CLZ- N-去甲基氯氮平比例的吸烟独立分析重复了先前鉴定的第4号染色体上的基因座。在调整了“吸烟者”（61％）或“不吸烟者”患者的吸烟习惯后（39％），一个新的变异（rs28379954；次要T > C等位基因频率4.1％；CT 7.6％编码核因子1 B型（NFIB）的基因内的人类携带者与CLZ血清浓度降低显着相关（p  = 1.68×10 ^-8，beta = -0.376;解释方差7.63％）。在GWAS分析中，rs28379954与N-去甲基氯氮平浓度之间无显着相关性（p  = 5.63×10 ^-5）。携带者相对于rs28379954次要C等位基因的非携带者，低于300 nmol / L的CLZ TDM样品的比例显着更高[12.0％（95％CI：9.4–14.7）vs. 6.2％（95％CI：5.7–6.8） ，p <0.001]。我们在NFIB基因中发现了一种新的变异，与CLZ水平降低和亚治疗性血清浓度升高的风险有关。这保证了筛查此基因变异的临床相关性，也需要进行实验研究以研究NFIB参与CLZ药代动力学的生物学机制。