Teymouri Kowsar, Ebrahimi Mahbod, Chen Cheng C, Sriretnakumar Venuja, Mohiuddin Ayeshah G, Tiwari Arun K, Pouget Jennie G, Zai Clement C, Kennedy James L
Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Psychiatry Res. 2024 Dec;342:116202. doi: 10.1016/j.psychres.2024.116202. Epub 2024 Sep 23.
The complement component 4 (C4) gene, codes for two isotypes, C4A and C4B, and can exist in long or short forms (C4L and C4S). The C4AL variant has been associated with elevated schizophrenia (SCZ) risk. Here, we investigated the relationship between C4 variation and clinical outcomes in SCZ. N = 434 adults with SCZ or schizoaffective disorder were included in this retrospective study. A three-step genotyping workflow was performed to determine C4 copy number variants. These variants were tested for association with clinical outcome measures, including treatment-resistant SCZ (TRS), number of hospitalizations (NOH), and symptom severity (PANSS). Sex and ancestry stratified analyses were performed. We observed a marginally significant association between C4S and TRS in males only, and a negative association between C4S and NOH in the total sample. C4AS had negative association with NOH in males and non-Europeans. Lastly, C4A copy numbers and C4A predicted brain expression showed negative association with NOH in males only. Our study provides further support for sex-specific effect of C4 on SCZ clinical outcomes, and also suggests that C4S and C4AS might have a protective effect against increased severity. C4 could potentially serve as a genetic biomarker in the future, however, more research is required.
补体成分4（C4）基因编码两种同种型，即C4A和C4B，并且可以以长或短形式（C4L和C4S）存在。C4AL变体与精神分裂症（SCZ）风险升高有关。在此，我们研究了SCZ中C4变异与临床结局之间的关系。本回顾性研究纳入了434名患有SCZ或分裂情感性障碍的成年人。进行了三步基因分型工作流程以确定C4拷贝数变异。测试了这些变异与临床结局指标的相关性，包括难治性SCZ（TRS）、住院次数（NOH）和症状严重程度（PANSS）。进行了性别和血统分层分析。我们仅在男性中观察到C4S与TRS之间存在边缘显著相关性，在总样本中C4S与NOH之间存在负相关性。C4AS在男性和非欧洲人中与NOH呈负相关。最后，仅在男性中C4A拷贝数和C4A预测的脑表达与NOH呈负相关。我们的研究为C4对SCZ临床结局的性别特异性效应提供了进一步支持，并且还表明C4S和C4AS可能对严重程度增加具有保护作用。C4未来有可能作为一种遗传生物标志物，然而，还需要更多的研究。
