Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology,Biological Psychiatry

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Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology
Biological Psychiatry ( IF 10.6 ) Pub Date : 2021-07-07 , DOI: 10.1016/j.biopsych.2021.06.021
Tania Da Silva ₁ , Elisa Guma ₂ , Sina Hafizi ₃ , Alex Koppel ₄ , Pablo Rusjan ₅ , James L Kennedy ₆ , Mallar M Chakravarty ₇ , Romina Mizrahi ₈

Affiliation

Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Computational Brain Anatomy Laboratory, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
Department of Psychiatry, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Tanenbaum Centre for Pharmacogenetics, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada; Department of Biological and Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Background

Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology.

Methods

Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [¹⁸F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS).

Results

Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO.

Conclusions

This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.

中文翻译：

基因预测的脑 C4A 表达与 TSPO 和海马形态有关

背景

免疫系统的改变，特别是C4A，与精神分裂症的病理生理学有关。C4A在临床前模型中促进小胶质细胞的突触消除；然而，目前尚不清楚这个过程是否也存在于活人身上，以及它如何影响大脑形态。

方法

参与者（N = 111；33 名精神病患者、37 名临床高危个体和 41 名健康对照受试者）接受了 TSPO [ ¹⁸ F]FEPPA 正电子发射断层扫描和磁共振成像扫描。脑C4A表达被遗传预测为 4 种结构元素（C4AL、C4BL、C4AS、C4BS）中每一种的剂量的函数。

结果

较高的基因预测脑C4A表达与较高的脑小胶质细胞标志物 (TSPO) 和改变的海马形态相关，包括减少的表面积和 CA1 区域的内侧位移。这项研究首次量化了临床高风险个体中基因预测的脑C4A表达，与健康对照受试者相比，临床高风险个体的C4A显着降低。我们还展示了性别对基因预测的大脑C4A表达的强烈影响以及性和大麻使用对大脑 TSPO 的影响。