Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?
Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?
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DOI：
10.1016/j.biopsych.2021.10.018
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发表时间：
2022-04-15
影响因子：
10.6
通讯作者：
Bray NJ
中科院分区：
文献类型：
--
作者：
Hall J;Bray NJ
对精神分裂症的大规模基因组研究已经确定了数百个赋予这种疾病风险的遗传位点。这一进展为确定该疾病的生物学基础和潜在的新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，外显子组测序分析的精神分裂症，以及功能基因组数据从出生前和出生后的大脑，突触的发展和功能的见解。这些数据为以下观点提供了有力的支持：大脑皮层、海马和其他边缘系统结构的γ-氨基丁酸能和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紊乱开始于子宫内，但在整个发育过程中持续存在，某些等位基因通过直接影响成年期的突触功能而赋予疾病风险。这一模型意味着，精神分裂症的新干预措施可能包括旨在增强发育期间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。
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.
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通过发育绘制精神分裂症突触可塑性受损的后果：不同临床特征的综合模型。
影响因子：
19.9
作者：
Forsyth JK;Lewis DA
通讯作者：
Lewis DA
影响因子：
11
作者：
Clifton NE;Pocklington AJ;Scholz B;Rees E;Walters JT;Kirov G;O'Donovan MC;Owen MJ;Wilkinson LS;Thomas KL;Hall J
通讯作者：
Hall J
影响因子：
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通讯作者：
Sullivan, P. F.
影响因子：
6.8
作者：
Clifton, Nicholas E.;Hannon, Eilis;Hall, Jeremy
通讯作者：
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影响因子：
5.5
作者：
Farmer, Laurel M.;Le, Brandy N.;Nelson, Deborah J.
通讯作者：
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