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Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?
Biological Psychiatry ( IF 9.6 ) Pub Date : 2021-10-29 , DOI: 10.1016/j.biopsych.2021.10.018
Jeremy Hall 1 , Nicholas J Bray 1
Affiliation  

Large-scale genomic studies of schizophrenia have identified hundreds of genetic loci conferring risk to the disorder. This progress offers an important route toward defining the biological basis of the condition and potentially developing new treatments. In this review, we discuss insights from recent genome-wide association study, copy number variant, and exome sequencing analyses of schizophrenia, together with functional genomics data from the pre- and postnatal brain, in relation to synaptic development and function. These data provide strong support for the view that synaptic dysfunction within glutamatergic and GABAergic (gamma-aminobutyric acidergic) neurons of the cerebral cortex, hippocampus, and other limbic structures is a central component of schizophrenia pathophysiology. Implicated genes and functional genomic data suggest that disturbances in synaptic connectivity associated with susceptibility to schizophrenia begin in utero but continue throughout development, with some alleles conferring risk to the disorder through direct effects on synaptic function in adulthood. This model implies that novel interventions for schizophrenia could include broad preventive approaches aimed at enhancing synaptic health during development as well as more targeted treatments aimed at correcting synaptic function in affected adults.



中文翻译:

精神分裂症基因组学:突触发育、成人突触可塑性或两者兼而有之?

精神分裂症的大规模基因组研究已经确定了数百个赋予该疾病风险的基因位点。这一进展为确定疾病的生物学基础和可能开发新的治疗方法提供了一条重要途径。在这篇综述中,我们讨论了最近对精神分裂症的全基因组关联研究、拷贝数变异和外显子组测序分析的见解,以及来自出生前和出生后大脑的功能基因组学数据,这些数据与突触发育和功能有关。这些数据有力地支持了以下观点:大脑皮层、海马和其他边缘结构的谷氨酸能和 GABA 能(γ-氨基丁酸能)神经元内的突触功能障碍是精神分裂症病理生理学的核心组成部分。相关基因和功能基因组数据表明,与精神分裂症易感性相关的突触连接障碍始于子宫内,但在整个发育过程中持续存在,其中一些等位基因通过直接影响成年期的突触功能而赋予该疾病的风险。该模型意味着精神分裂症的新干预措施可能包括旨在增强发育过程中突触健康的广泛预防方法,以及旨在纠正受影响成年人突触功能的更有针对性的治疗。

更新日期:2021-10-29
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