Functional genomic investigation of complement signaling in the human brain

人脑补体信号传导的功能基因组研究

• 批准号: 10389218
• 负责人: Minsoo Kim
• 金额: $ 3.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2022-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389218
• 关键词: 10 year old; Address; Adolescent; Adult; Alzheimer' s Disease; Autopsy; Behavior; Biological; Bipolar Disorder; Brain; Brain imaging; Child Behavior Checklist; Chromosome 6; Classical Complement Pathway; Complement; Complement Component Gene; Complex; Data; Data Set; Development; Diagnostic; Dimensions; Disease; Distal; Environmental Risk Factor; Exhibits; Functional disorder; Gene Expression; Genes; Genetic; Genomics; Genotype; Heritability; Human; Individual; Investigation; Logistic Regressions; Magnetic Resonance Imaging; Major Depressive Disorder; Major Histocompatibility Complex; Measures; Mediating; Mendelian randomization; Mental Health; Mental disorders; Mentorship; Mission; National Institute of Mental Health; Natural Immunity; Pathway interactions; Pattern; Phenotype; Play; Process; Prospective cohort; Public Health; Quantitative Trait Loci; Resources; Risk; Risk Factors; Role; Sampling; Schizophrenia; Sex Bias; Sex Factors; Signal Pathway; Signal Transduction; Structure; System; Testing; Therapeutic; Thick; Training; Up-Regulation; Variant; Weight; Work; autism spectrum disorder; base; case control; cognitive development; complement system; differential expression; disorder risk; doctoral student; functional genomics; gene complementation; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; genomic data; indexing; individuals with autism spectrum disorder; insight; large scale data; neurobehavioral; neurobiological mechanism; neuroimaging; neuropsychiatric disorder; neuropsychiatry; novel; psychiatric genomics; psychogenetics; rare variant; schizophrenia risk; sex; success; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics

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.

项目摘要/摘要 大规模基因组关联研究（GWAS）已成功鉴定出数百种遗传风险 与常见但复杂的神经精神疾病相关的因素。增加的表达 成分4A（C4A）是精神分裂症（SCZ）病理生理学中隐含的一个因素。 但是，人脑中C4A的确切生物学机制以及更广泛的完成 系统 - 由于其适度的效果尺寸和缺乏适当的效果，SCZ的关注风险仍然不清楚 实验系统充分概括了与疾病相关的环境。此外，最近的工作有 揭示了神经精神疾病的实质性遗传重叠，对多大程度知之甚少 完成系统有助于其他具有共同遗传影响的疾病。在这里，我们建议 全面的功能基因组分析集，以研究完成系统的失调 人脑及其与自闭症谱系障碍（ASD），SCZ，躁郁症（BD）和 重度抑郁症（MDD）。鉴于C4A与SCZ的强度和显着的遗传 这些疾病之间的相关性，我们假设完成系统将广泛参与 神经精神疾病的病理生理学。为了检验这一假设，我们将基于我们最近的工作 编译大规模基因型阵列和RNA-seq数据集的精神码 样品，包括数百个ASD，SCZ，BD和MDD的人。利用此数据集，我们将 评估这四种疾病中完成系统的病例对照差异表达（AIM 1）。下一个， 我们将确定完成系统基因表达的遗传调节因子，并确定其与 已建立的神经精神遗传危险因素（AIM 2）。最后，开始阐明 人脑发育过程中的补体系统，我们将研究完成系统基因 表达与青少年脑认知发展的大脑结构和行为的变异有关 （ABCD）研究以及这些关系如何受到性别和环境因素的调节（AIM 3）。拍摄 这些目标一起将系统地表征完成系统对广泛的整体贡献 一系列遗传相关的神经精神疾病范围，这与NIMH的使命一致 神经生物学机制是精神疾病的基础。这些研究将由MD- Minsoo Kim进行 加州大学洛杉矶分校（UCLA）的博士生将提供精神遗传学和基因组学的全面培训。指导 将由博士提供。迈克尔·J·甘达（Michael J. Gandal）和丹尼尔·H·格斯温德（Daniel H. 基因组学和神经行为遗传学。