Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St. Suite 820, Houston, TX, 77030, USA.
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
BMC Med Genomics. 2020 Dec 28;13(Suppl 11):192. doi: 10.1186/s12920-020-00832-8.
Psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BIP), major depressive disorder (MDD), attention deficit-hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) are often related to brain development. Both shared and unique biological and neurodevelopmental processes have been reported to be involved in these disorders.
In this work, we developed an integrative analysis framework to seek for the sensitive spatiotemporal point during brain development underlying each disorder. Specifically, we first identified spatiotemporal gene co-expression modules for four brain regions three developmental stages (prenatal, birth to 11 years old, and older than 13 years), totaling 12 spatiotemporal sites. By integrating GWAS summary statistics and the spatiotemporal co-expression modules, we characterized the risk genes and their co-expression partners for five disorders.
We found that SCZ and BIP, ASD and ADHD tend to cluster with each other and keep a distance from other psychiatric disorders. At the gene level, we identified several genes that were shared among the most significant modules, such as CTNNB1 and LNX1, and a hub gene, ATF2, in multiple modules. Moreover, we pinpointed two spatiotemporal points in the prenatal stage with active expression activities and highlighted one postnatal point for BIP. Further functional analysis of the disorder-related module highlighted the apoptotic signaling pathway for ASD and the immune-related and cell-cell adhesion function for SCZ, respectively.
Our study demonstrated the dynamic changes of disorder-related genes at the network level, shedding light on the spatiotemporal regulation during brain development.
精神疾病，如精神分裂症（SCZ）、双相情感障碍（BIP）、重度抑郁症（MDD）、注意缺陷多动障碍（ADHD）和自闭症谱系障碍（ASD），通常与大脑发育有关。这些疾病涉及到共同和独特的生物和神经发育过程。
在这项工作中，我们开发了一个综合分析框架，以寻找每种疾病大脑发育过程中敏感的时空点。具体来说，我们首先确定了四个脑区三个发育阶段（产前、11 岁以下和 13 岁以上）的时空基因共表达模块，总共 12 个时空位点。通过整合 GWAS 汇总统计数据和时空共表达模块，我们对五种疾病的风险基因及其共表达伙伴进行了特征描述。
我们发现 SCZ 和 BIP、ASD 和 ADHD 倾向于相互聚类，与其他精神疾病保持距离。在基因水平上，我们确定了几个在大多数显著模块中共享的基因，如 CTNNB1 和 LNX1，以及多个模块中的一个枢纽基因 ATF2。此外，我们在产前阶段确定了两个具有活跃表达活动的时空点，并突出了 BIP 的一个产后点。对疾病相关模块的进一步功能分析突出了 ASD 的凋亡信号通路和 SCZ 的免疫相关和细胞-细胞黏附功能。
我们的研究在网络水平上展示了与疾病相关基因的动态变化，为大脑发育过程中的时空调节提供了线索。
