Functional genomic investigation of complement signaling in the human brain

项目摘要/摘要 大规模全基因组关联研究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障碍相关的因素。补体表达增加 组分4A(C4a)就是与精神分裂症(SCZ)病理生理学有关的因子之一。 然而，C4a-和更广泛的补体在人脑中的确切生物学机制 SCZ的系统风险仍然不清楚，因为它的影响规模不大，而且缺乏适当的 实验系统充分概括了与疾病相关的背景。此外，鉴于最近的工作已经 揭示了神经精神障碍之间的大量基因重叠，对其程度知之甚少 补体系统与其他具有共同遗传影响的疾病有关。在这里，我们提出一种 一套全面的功能基因组分析，以研究补体系统的失调 人脑及其与自闭症谱系障碍(ASD)、SCZ、双相情感障碍(BD)风险的关系 抑郁症(MDD)。鉴于C4A与SCZ之间的联系以及显著的遗传 这些紊乱之间的相关性，我们假设补体系统将广泛参与 神经精神障碍的病理生理学。为了验证这一假设，我们将在最近的工作基础上使用 将汇编约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。利用此数据集，我们将 评估病例对照补体系统在这四种疾病中的差异表达(目标1)。下一首, 我们将确定补体系统基因表达的遗传调节因素，并确定它们与 已确定的神经精神病学遗传危险因素(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是如何 青少年脑认知发育中表达与脑结构和行为变异的关系 (ABCD)研究以及性别和环境因素如何调节这些关系(目标3)。已被占用 总而言之，这些目标将系统地表征补充制度对广泛的 一系列与遗传相关的神经精神障碍，这与NIMH澄清 精神疾病背后的神经生物学机制。这些研究将由医学博士金敏秀进行。 加州大学洛杉矶分校的博士生，将提供精神病学遗传学和基因组学方面的综合培训。导师制 将由交叉障碍领域的专家Michael J.Gandal博士和Daniel H.Geschind博士提供 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.