2/2 - Identification and Validation of Expression Quantitative Trait Loci (eQTLs) in discrete cell types across human brain development

2/2 - 人脑发育过程中离散细胞类型中表达数量性状位点 (eQTL) 的识别和验证

• 批准号: 10531268
• 负责人: Stephan Sanders
• 金额: $ 44.52万
• 依托单位: UNIVERSITY OF OXFORD
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531268
• 关键词: Adolescence; Adult; Affect; Age of Onset; Alleles; Alzheimer' s Disease; Behavior; Biological; Bipolar Disorder; Brain; Brain region; Cell Nucleus; Cells; Chromatin; Code; Communities; Complement; Copy Number Polymorphism; Corpus striatum structure; DNA; Data; Data Set; Databases; Development; Disease; Epigenetic Process; Etiology; Exhibits; Fetal Development; Gene Expression; Gene Expression Profile; Gene Frequency; Generations; Genes; Genetic; Genotype; Human; Human Genome; Individual; Link; Methods; Neurobiology; Neurodevelopmental Disorder; Neurosciences; Pattern; Prefrontal Cortex; Prevalence; Process; Property; Proteins; Quantitative Trait Loci; RNA Splicing; Regulatory Element; Resources; Risk; Role; Sampling; Schizophrenia; Single Nucleotide Polymorphism; Source; Specificity; Spliced Genes; System; Tissues; Untranslated RNA; Validation; Variant; autism spectrum disorder; brain cell; brain tissue; cell type; cohort; computerized tools; data integration; disorder risk; epigenetic marker; experimental study; fetal; functional genomics; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genomic data; genomic locus; genomic variation; histone modification; insertion/deletion mutation; insight; neurodevelopment; neuropsychiatric disorder; next generation; novel; postnatal development; prenatal; rare variant; risk variant; sex; single nucleus RNA-sequencing; spatiotemporal; trait; transcriptome; transcriptome sequencing; transcriptomic profiling; whole genome

ABSTRACT Functional genomic analyses of the developing human brain have revealed highly dynamic spatiotemporal patterns of gene expression and epigenetic changes during prenatal and early postnatal development and across brain regions. Disruptions of these developmentally dynamic processes have been implicated by numerous complementary analyses in the etiology of multiple neurodevelopmental and neuropsychiatric disorders. Expression quantitative trait loci (eQTLs), along with splicing quantitative trait loci (sQTLs) and structural variant quantitative trait loci (svQTLs), are genomic variants that differ between individuals, with these differences correlating with functional changes to gene expression or splicing behavior. Many of these QTLs show specificity to tissues, brain regions, developmental stages, or cell types, and a proportion overlap with known genetic risk factors of human disorders. Here, we propose to pursue three integrated Aims, including whole-genome sequencing and both bulk tissue and single-nuclei RNA sequencing, to identify genomic variants, eQTL/sQTL/svQTLs, and patterns of gene expression and co-expression in two regions of the human brain across mid-fetal development through to adolescence. In addition, we will apply novel and newly developed computational tools to associate these QTLs with specific cell types and loci or genes implicated in neuropsychiatric disorders. By so doing we will augment, and dramatically expand upon, earlier efforts to understand QTLs and their roles in neural development, function, and neuropsychiatric disorders.

摘要 对发育中的人脑进行的功能基因组分析揭示了高度动态的时空 出生前和出生后早期发育过程中基因表达和表观遗传变化的模式 横跨大脑各区域。这些发育动态过程的中断被牵连到 多种神经发育和神经精神疾病病因的大量互补分析 精神错乱。表达数量性状基因座(EQTL)、剪接数量性状基因座(SQTL)和 结构变异数量性状基因座(SvQTL)是个体间不同的基因组变异，具有 这些差异与基因表达或剪接行为的功能变化有关。其中许多 QTL表现出组织、脑区域、发育阶段或细胞类型的特异性，并且比例重叠 已知人类疾病的遗传风险因素。在这里，我们提出追求三个综合目标， 包括全基因组测序以及整体组织和单核RNA测序，以鉴定 基因组变异、eQTL/sQTL/svQTL以及两个区域的基因表达和共表达模式 人类大脑从胎儿中期发育到青春期。此外，我们将应用新颖和 新开发的计算工具将这些QTL与特定的细胞类型和基因座或基因联系起来 与神经精神障碍有牵连。通过这样做，我们将增强并戏剧性地扩展更早的 努力了解QTL及其在神经发育、功能和神经精神障碍中的作用。