Isoform-level probabilistic transcriptome-wide association to undercover neurogenetic mechanisms underlying complex psychiatric traits

同种型水平的概率转录组范围与复杂精神特征背后的秘密神经发生机制的关联

• 批准号: 10079506
• 负责人: Michael Gandal
• 金额: $ 68.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-03 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079506
• 关键词: Address; Adult; Affect; Alternative Splicing; Area; Biological; Biological Process; Brain; CRISPR/Cas technology; Candidate Disease Gene; Cell Line; Cells; Communities; Complex; Data; Development; Disease; Ensure; Event; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genetic Variation; Genets; Genome engineering; Genomic approach; Genomics; Genotype; Heritability; Human; Individual; Intervention; Knock-in; Link; Linkage Disequilibrium; Mental disorders; Methods; Neurobiology; Neurons; Pathogenesis; Pattern; Phenotype; Protein Isoforms; Proteomics; Quality Control; Quantitative Trait Loci; RNA; RNA Splicing; Regulation; Reporting; Reproducibility of Results; Resolution; Resources; Risk; Sampling; Schizophrenia; Science; Signal Transduction; Specificity; TCF7L2 gene; Techniques; Therapeutic Intervention; Tissue-Specific Gene Expression; Tissues; Transcript; Uncertainty; Variant; Work; autism spectrum disorder; base; cell type; differential expression; disorder risk; fetal; functional genomics; genetic variant; genome wide association study; genome-wide; genomic data; genomic locus; insight; nerve stem cell; neurobiological mechanism; neurogenetics; neuropsychiatry; new therapeutic target; novel; precision medicine; repaired; risk variant; targeted treatment; therapeutic development; trait; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT As large-scale genome-wide association studies (GWAS) rapidly identify associations with neurodevelopmental and psychiatric traits, the major defining challenge of the post-GWAS era is to rigorously define the neurobiological mechanisms underlying disease-associated genetic variation at scale. To this end, we and others have recently developed methods to directly integrate GWAS results with large-scale tissue-specific expression quantitative trait loci (eQTL) reference panels, enabling a transcriptome-wide association study (TWAS) – a powerful approach to identify genes whose expression is associated with genetic risk for disease. In parallel, emerging evidence has strongly implicated alternative splicing – a form of genetic regulation capable of generating an exponential number of unique RNA transcript isoforms from a single gene – as an important mechanism that exhibits dynamic patterns across development and is disrupted in the brains on individuals affected by psychiatric diseases, including autism and schizophrenia. Yet, no studies have systematically characterized the genetic regulation of isoform expression in human brain or its association with genetic risk for psychiatric disorders. This proposal seeks to develop a novel, isoform-level TWAS approach (iso-TWAS) to identify transcript-isoforms whose cis-regulated expression is associated with psychiatric disease risk. We will compile a large-scale functional genomic reference panel incorporating genotype and isoform quantifications from RNA-seq data of more than 3800 human brain samples, which we will leverage to perform iso-TWAS along with traditional gene-level TWAS for a host of neuropsychiatric traits. We will directly integrate isoform quantification uncertainties as well as probabilistic fine-mapping within our iso-TWAS framework, in order to ensure the robustness of resulting associations. We hypothesize that isoform-level characterization will provide substantially greater resolution to detect candidate biological mechanisms underlying psychiatric GWAS loci. Finally, predicted SNP-isoform-disease associations will be experimentally validated using genome-engineering in primary human neural progenitor cell (phNPC) lines followed by long-read RNA-sequencing and detailed cellular phenotyping. Together, these studies will systematically characterize a critical, yet underexplored area of genomic regulation in human brain, thereby providing novel insights into psychiatric disease mechanisms and identifying potential neurobiological targets for therapeutic development and intervention.

项目概要/摘要 随着大规模全基因组关联研究（GWAS）迅速识别与神经发育的关联 和精神特征，后 GWAS 时代的主要挑战是严格定义 为此，我们和其他人研究了与疾病相关的大规模遗传变异的神经生物学机制。 最近开发了将 GWAS 结果与大规模组织特异性表达直接整合的方法 数量性状位点 (eQTL) 参考面板，支持全转录组关联研究 (TWAS) – 同时，识别其表达与疾病遗传风险相关的基因的强大方法。 新出现的证据强烈暗示选择性剪接——一种基因调控形式，能够 从单个基因产生指数数量的独特 RNA 转录亚型——作为一个重要的 在发育过程中表现出动态模式并在个体大脑中被破坏的机制 然而，还没有系统性的研究表明，儿童是否会受到精神疾病的影响，包括自闭症和精神分裂症。 表征了人脑中异构体表达的遗传调控或其与遗传风险的关系 该提案旨在开发一种新颖的异构体水平 TWAS 方法（iso-TWAS）来治疗精神疾病。 我们将鉴定其顺式调节表达与精神疾病风险相关的转录亚型。 编制包含基因型和异构体定量的大规模功能基因组参考面板 来自 3800 多个人脑样本的 RNA-seq 数据，我们将利用这些数据来执行 iso-TWAS 我们将直接整合多种神经精神特征的传统基因级 TWAS。 我们的 iso-TWAS 框架内的量化不确定性以及概率精细映射，以便 确保所得关联的稳健性。我们发现异构体水平的表征将提供。 显着提高检测精神科 GWAS 位点潜在生物学机制的分辨率。 最后，预测的 SNP-亚型-疾病关联将使用基因组工程进行实验验证 在原代人类神经祖细胞 (phNPC) 系中进行长读 RNA 测序和详细分析 这些研究将共同​​系统地描述一个关键但尚未充分探索的领域。 人脑基因组调控的研究，从而为精神疾病机制和 确定治疗开发和干预的潜在神经生物学靶点。