MRC Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; Neuroscience & Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
Biol Psychiatry. 2022 Apr 15;91(8):709-717. doi: 10.1016/j.biopsych.2021.10.018. Epub 2021 Oct 29.
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.
大规模的精神分裂症基因组研究已经确定了数百个遗传风险位点。这一进展为定义该疾病的生物学基础并可能开发新的治疗方法提供了重要途径。在这篇综述中，我们讨论了最近的全基因组关联研究、拷贝数变异和外显子组测序分析，以及来自产前和产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。这些数据为以下观点提供了强有力的支持：大脑皮层、海马体和其他边缘结构中谷氨酸能和 GABA 能（γ-氨基丁酸能）神经元的突触功能障碍是精神分裂症病理生理学的一个核心组成部分。涉及的基因和功能基因组学数据表明，与精神分裂症易感性相关的突触连接紊乱始于子宫内，但在整个发育过程中持续存在，一些等位基因通过对成年期突触功能的直接影响而对该疾病产生风险。该模型表明，精神分裂症的新干预措施可能包括广泛的预防措施，旨在增强发育过程中的突触健康，以及更有针对性的治疗方法，旨在纠正受影响成年人的突触功能。
