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) 是治疗精神分裂症的优质抗精神病药物，但表现出广泛的患者间药代动力学变异性。在这里，我们针对已知的吸烟习惯进行了 CLZ 血清浓度的全基因组关联研究 (GWAS)，吸烟习惯是降低 CLZ 水平的主要非遗传因素。该研究纳入了来自治疗药物监测 (TDM) 服务的 484 名患者，其中 10,283 份 CLZ 和N-去甲基氯氮平稳态血清浓度、处方剂量、联合用药和已知吸烟习惯（ n = 422；9284 份血清样本）。 GWAS 分析以吸烟习惯和不吸烟习惯作为协变量进行，其中根据 TDM 服务中应用的目标 CLZ 浓度范围（300-2500 nmol/L）评估可能的命中。 N-去甲基氯氮平血清浓度和 CLZ 与N-去甲基氯氮平比率的独立于吸烟的分析复制了之前在 4 号染色体上确定的位点。在对确认为“吸烟者”(61%) 或“非吸烟者”的患者的吸烟习惯进行调整后(39%)，编码核因子 1 B 型 ( NFIB ) 的基因中的一种新变异（ rs28379954 ；次要T > C等位基因频率 4.1%；人群中有 7.6% CT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%）。 GWAS 分析中， rs28379954与N-去甲基氯氮平浓度之间没有显着相关性 ( p = 5.63 × 10 ^-5 )。与对照组相比，携带者中 CLZ TDM 样品低于 300 nmol/L 的比例显着更高。 rs28379954次要C等位基因的非携带者 [12.0% (95% CI: 9.4–14.7) vs. 6.2% (95% CI: 5.7–6.8), p < 0.001]。我们发现了NFIB基因中的一种新变异，该变异与 CLZ 水平降低和低于治疗血清浓度的风险增加相关。这需要测试该基因变异筛查的临床相关性，也需要进行实验研究来调查 NFIB 参与 CLZ 药代动力学的生物学机制。