Functional genomic investigation of complement signaling in the human brain

项目总结/摘要 大规模的全基因组关联研究（GWAS）已经成功地确定了数百种遗传风险， 与常见但复杂的神经精神疾病相关的因素。补体表达增加 组分4A（C4 A）是一种与精神分裂症（SCZ）病理生理学有关的因子。 然而，确切的生物学机制在人类大脑中通过C4 A-和更广泛的补充， SCZ的系统赋予风险仍然不清楚，由于其适度的效应大小和缺乏适当的 实验系统充分概括了疾病相关的背景。此外，尽管最近的工作 揭示了大量的遗传重叠在神经精神疾病，很少有人知道的程度， 补体系统导致具有共同遗传影响的其它病症。在这里，我们提出一个 一套全面的功能基因组分析，以调查补体系统的失调， 人类大脑及其与自闭症谱系障碍（ASD）、SCZ、双相情感障碍（BD）和 重度抑郁症（MDD）。鉴于C4 A与SCZ的关联强度以及显着的遗传性， 这些疾病之间的相关性，我们假设补体系统将广泛参与这些疾病的发生。 神经精神障碍的病理生理学。为了验证这一假设，我们将建立在我们最近的工作， PsychENCODE编译了约3，000个成人大脑的大规模基因型阵列和RNA-seq数据集 样本，包括数百名ASD，SCZ，BD和MDD患者。利用这个数据集，我们将 评估补体系统在这四种疾病中的病例对照差异表达（目的1）。接下来， 我们将鉴定补体系统基因表达的遗传调节因子，并确定它们与 建立神经精神遗传危险因素（目标2）。最后，为了开始阐明 补体系统在人脑发育过程中，我们将研究补体系统基因如何 表达与青少年大脑认知发展中大脑结构和行为的变化有关 （ABCD）研究以及这些关系如何受到性别和环境因素的调节（目标3）。采取 总之，这些目标将系统地描述补体系统对广泛的 一系列遗传相关的神经精神疾病，这符合NIMH的使命，以阐明 精神疾病的神经生物学机制这些研究将由医学博士Minsoo Kim进行- 他是加州大学洛杉矶分校的博士生，将提供精神病遗传学和基因组学方面的全面培训。指导 将由Michael J. Gandal博士和丹尼尔H. Geschwind，交叉紊乱领域的专家 基因组学和神经行为遗传学。

PROJECT SUMMARY/ABSTRACT Large-scale genome-wide association studies (GWAS) have successfully identified hundreds of genetic risk factors associated with common but complex neuropsychiatric disorders. Increased expression of complement component 4A (C4A) is one such factor that has been implicated in schizophrenia (SCZ) pathophysiology. However, the exact biological mechanisms in the human brain through which C4A—and the broader complement system—confer risk for SCZ remains unclear, due to its modest effect size and the lack of an appropriate experimental system adequately recapitulating disease-relevant context. Furthermore, whereas recent work has revealed substantial genetic overlap across neuropsychiatric disorders, little is known about the extent to which the complement system contributes to other disorders with shared genetic influences. Here, we propose a comprehensive set of functional genomic analyses to investigate the dysregulation of the complement system in the human brain and its relation to risk for autism spectrum disorder (ASD), SCZ, bipolar disorder (BD), and major depressive disorder (MDD). Given the strength of the C4A association with SCZ and the significant genetic correlations among these disorders, we hypothesize that the complement system will be broadly involved in the pathophysiology of neuropsychiatric disorders. To test this hypothesis, we will build upon our recent work with PsychENCODE to compile a large-scale genotype array and RNA-seq dataset of ~3,000 adult human brain samples, including several hundred individuals with ASD, SCZ, BD, and MDD. Leveraging this dataset, we will assess case-control differential expression of the complement system across these four disorders (Aim 1). Next, we will identify genetic regulators of complement system gene expression and determine their relation to established neuropsychiatric genetic risk factors (Aim 2). Finally, to begin to elucidate the functional role of the complement system during human brain development, we will examine how complement system gene expression is related to variability in brain structure and behavior in the Adolescent Brain Cognitive Development (ABCD) study and how these relationships are moderated by sex and environmental factors (Aim 3). Taken together, these aims will systematically characterize the overall contribution of the complement system to a broad range of genetically related neuropsychiatric disorders, which is in line with the NIMH mission to elucidate the neurobiological mechanisms underlying mental illnesses. These studies will be conducted by Minsoo Kim, a MD- PhD student at UCLA, and will provide comprehensive training in psychiatric genetics and genomics. Mentorship will be provided by Drs. Michael J. Gandal and Daniel H. Geschwind, experts in the fields of cross-disorder genomics and neurobehavioral genetics.