Deciphering the role of histone methyltransferase SETD1A in schizophrenia susceptibility

项目总结 精神分裂症患者近期全外显子组测序研究的收集数据 证实了基因破坏性新生功能丧失突变的显著丰富 并导致了编码组蛋白的SETD1A的贡献的鉴定 甲基转移酶。值得注意的是，SETD1A突变会使疾病风险大幅增加， 这为疾病建模提供了一个很好的起点。 明确识别SETD1A为SCZ风险基因强调了 神经基因调控在精神分裂症的遗传结构中扮演的角色， 与越来越多的证据支持监管的重要作用是一致的 神经精神疾病风险中常见和罕见的变异。这一发现也是 与多条证据一致，表明组蛋白甲基化 与SCZ广泛相关，包括最近观察到的组蛋白甲基化 在4,939条生物途径中显示出最强的统计丰度 精神障碍的数据。无论是常见的还是罕见的风险变量 这一特定生物途径中的聚集体突出了它在糖尿病病因中的重要性。 精神分裂症。然而，目前还不清楚如何将无处不在的 分子过程，如染色质修饰成一种机械性和疾病- 具体洞察力。在这一点上，SETD1A发现提供了一个句柄、一个起点 以此为基础建立模型并检验假设。 这项提案的目标是解决染色质如何 调节缺陷通过以下方式在SCZ的发病机制中发挥作用：(I)研究 SETD1A对小鼠认知和突触功能的发育需求及其机制 由其缺陷影响的神经回路的性质(II)识别直接神经元 SETD1A在前额叶皮质的靶点和(Iii)产生和分析人类 SETD1a缺乏的皮质神经元。 拟议的精神疾病染色质调节研究的最终目标是 要了解遗传脆弱性何时/何地/如何影响基因表达， 并塑造大脑的电路和功能。拟议的研究还将揭示一个宿主 精神分裂症候选基因，并有望在我们的 对衰弱的精神疾病的理解、诊断和治疗，例如 精神分裂症。

PROJECT SUMMARY Collective data from recent whole exome sequencing studies in schizophrenia confirmed a prominent enrichment of gene-disruptive de novo loss-of-function mutations and led to the identification of the contribution of SETD1A, which encodes for a histone methyltransferase. Notably, SETD1A mutations confer a large increase in disease risk, which provides a good starting point for disease modeling. Unambiguous identification of SETD1A as a SCZ risk gene emphasizes the important role that neural gene regulation plays in the genetic architecture of schizophrenia, consistent with accumulating evidence supporting an important role of regulatory common and rare variants in neuropsychiatric disease risk. This finding is also consistent with several lines of evidence suggesting that histone methylation is more broadly relevant to SCZ including the recent observation that histone methylation showed the strongest statistical enrichment among 4,939 biological pathways in GWAS data of psychiatric disorders. The fact that both common and rare risk variants aggregate in this particular biological pathway highlights its importance for the etiology of schizophrenia. However it is not clear at this stage how to translate a ubiquitous molecular process such as chromatin modification into a mechanistic and disease- specific insight. In this regard, the SETD1A finding provides a handle, a starting point from which to build a model and test hypotheses. The goal of this proposal is to address the critical question of how chromatin regulation deficits play a role in the pathogenesis of SCZ by (i) investigating the developmental requirement of Setd1a on cognitive and synaptic function in mice and the nature of the neural circuits affected by its deficiency (ii) identifying direct neuronal targets of Setd1a in the prefrontal cortex and (iii) generating and analyzing human SETD1A-deficient cortical neurons. The ultimate goal of the proposed studies of chromatin regulation in mental illness is to understand when/where/how genetic vulnerabilities affect gene expression in the brain and shape brain circuitry and function. The proposed studies will also reveal a host of schizophrenia candidate genes and promise important advances in our understanding, diagnosis, and treatment of debilitating psychiatric disorders, such as schizophrenia.