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: 10738989
• 负责人: Michael Gandal
• 金额: $ 63.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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/10738989
• 关键词: Address; Adult; Affect; Alternative Splicing; Area; Biological; Biological Process; Brain; CRISPR/Cas technology; Candidate Disease Gene; Cell Line; Cells; Chromosome Mapping; 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; Maps; 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; candidate validation; cell type; differential expression; disorder risk; fetal; functional genomics; genetic variant; genome resource; 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; transcriptomic profiling; 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.

项目总结/文摘