Department of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain Center, Utrecht, The Netherlands.
Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Brain Center, Utrecht, The Netherlands.
Transl Psychiatry. 2022 Apr 7;12(1):145. doi: 10.1038/s41398-022-01884-3.
Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.
氯氮平是治疗抵抗性精神分裂症患者最有效的抗精神病药物。然而，反应高度可变，这种可变性的潜在遗传基础仍然未知。在这里，我们进行了多基因风险评分（PRS）分析，以估计PRS（R2）解释氯氮平治疗患者症状严重程度的差异量，并检查了症状严重程度与基因型预测的 CYP1A2、CYP2D6 和 CYP2C19 酶活性之间的关联。进行了全基因组关联（GWA）分析以探索与症状严重程度相关的基因座。一个包含 804 名（经过质量控制后 N=684）精神分裂症谱系障碍患者的多中心队列，使用阳性和阴性综合征量表和/或临床总体印象严重程度量表（CGI-S）进行了横断面评估。进行了 GWA 和 PRS 回归分析。计算了基因型预测的 CYP1A2、CYP2D6 和 CYP2C19 酶活性。精神分裂症 PRS 与低症状严重程度最显著和正相关（p=1.03×10-5；R2=1.85）。跨疾病 PRS 也与较低的 CGI-S 评分呈正相关（p=0.01；R2=0.81）。与最低 tertile 相比，处于最高精神分裂症 PRS tertile 的患者低症状严重程度的概率增加了 1.94 倍（p=6.84×10-5）。较高的基因型预测 CYP2C19 酶活性与较低的症状严重程度独立相关（p=8.44×10-5）。虽然没有基因座超过全基因组显著性阈值，但 NFIB 内的 rs1923778 与症状严重程度显示出暗示性关联（p=3.78×10-5）。我们表明，高精神分裂症 PRS 和基因型预测 CYP2C19 酶活性与氯氮平治疗个体的低症状严重程度独立相关。我们的研究结果为未来的精神药理学项目研究 PRS 和基因型预测 CYP 活性在精神分裂症中的潜在应用开辟了途径。
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