Fine-mapping psychiatricdisease variants that affect post-transcriptional gene regulation

精细绘制影响转录后基因调控的精神疾病变异

基本信息

  • 批准号:
    10445082
  • 负责人:
  • 金额:
    $ 72.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-05 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Neuropsychiatric disorders (NPD) such as schizophrenia (SZ), autism spectrum disorders (ASD) and bipolar disorders (BD) are remarkably common, with SZ alone affecting nearly three million Americans. Despite more than fifty years of research, no cures exist for these conditions and the standard of treatment remains unsatisfactory. Genome-wide association studies (GWAS) indicate that, in addition to highly penetrant rare mutations, NPD risk also reflects the impact of hundreds of common single nucleotide polymorphisms with small effect sizes. A major challenge in the field has been illuminating the pathways connecting these genetic variants (the vast majority of which fall in non-coding sequences) to target genes and causal cellular phenotypes. To understand how these myriad risk loci causally contribute to disease risk, it is essential to screen for putatively causal variant(s) and determine how they influence gene expression, which has been shown to be cell-type specific, as well as cellular function. Recent evidence has emerged indicating a substantial contribution of RNA splicing variation to heritability across many complex genetic diseases, including SZ. Based on our preliminary analyses and the work of others, we hypothesize that a substantial proportion of NPD GWAS loci exert their pathogenic effects on neuronal function by impacting RNA: its structure, modifications, protein interactions and splicing. To test this, we will apply novel tools and machine learning methods to predict and quantify RNA splicing in the largest SZ, ASD and BD GWAS, in order to predict splicing quantitative trait loci (sQTLs, Aim 1). To confirm true effects on exon inclusion independently in glutamatergic and GABAergic neurons (i.e., the major cell-types impacted in NPD), up to several thousand of the predicted splice variants will be tested by a massively parallel reporter assay, MaPSy (Aim 2). Finally, in order to evaluate the cell-type-specific impact of putative causal sQTLs identified in Aims 1 and 2 on neuronal maturation and synaptic function, we will use CRISPR gene editing to engineer these mutations within human induced pluripotent stem cell (hiPSC)-based models of both neural cell types (Aim 3). Our overarching goal is to map and functionally evaluate the NPD-GWAS loci that impact alternative splicing and neuronal function. Our work may impact the field by delivering new insights into the role of common variants in NPD pathophysiology, which could inform ways of improving diagnostics, predicting clinical trajectories, and developing novel therapeutic interventions.
项目总结

项目成果

期刊论文数量(0)
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William G Fairbrother其他文献

William G Fairbrother的其他文献

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{{ truncateString('William G Fairbrother', 18)}}的其他基金

Fine-mapping psychiatric disease variants that affect post-transcriptional gene regulation
精细绘制影响转录后基因调控的精神疾病变异
  • 批准号:
    10415485
  • 财政年份:
    2021
  • 资助金额:
    $ 72.94万
  • 项目类别:
Discovering Splicing Defects in Human Genes
发现人类基因中的剪接缺陷
  • 批准号:
    10753767
  • 财政年份:
    2018
  • 资助金额:
    $ 72.94万
  • 项目类别:
Discovering Splicing Defects in Human Genes
发现人类基因中的剪接缺陷
  • 批准号:
    9920014
  • 财政年份:
    2018
  • 资助金额:
    $ 72.94万
  • 项目类别:
Discovering Splicing Defects in Human Genes
发现人类基因中的剪接缺陷
  • 批准号:
    10222718
  • 财政年份:
    2018
  • 资助金额:
    $ 72.94万
  • 项目类别:
Discovering Splicing Defects in Human Genes
发现人类基因中的剪接缺陷
  • 批准号:
    9769075
  • 财政年份:
    2018
  • 资助金额:
    $ 72.94万
  • 项目类别:
A genomic approach to studying the life cycle of intron lariats
研究内含子套索生命周期的基因组方法
  • 批准号:
    10155500
  • 财政年份:
    2014
  • 资助金额:
    $ 72.94万
  • 项目类别:
A genomic approach to studying the life cycle of intron lariats
研究内含子套索生命周期的基因组方法
  • 批准号:
    10335280
  • 财政年份:
    2014
  • 资助金额:
    $ 72.94万
  • 项目类别:
A genomic approach to studying the life cycle of intron lariats
研究内含子套索生命周期的基因组方法
  • 批准号:
    10251555
  • 财政年份:
    2014
  • 资助金额:
    $ 72.94万
  • 项目类别:
A genomic approach to studying the life cycle of intron lariats
研究内含子套索生命周期的基因组方法
  • 批准号:
    10548251
  • 财政年份:
    2014
  • 资助金额:
    $ 72.94万
  • 项目类别:
A genomic approach to studying the life cycle of intron lariats
研究内含子套索生命周期的基因组方法
  • 批准号:
    9043905
  • 财政年份:
    2014
  • 资助金额:
    $ 72.94万
  • 项目类别:

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非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
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