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
- 来源:
- 关键词:AffectAllelesAlternative SplicingAlzheimer&aposs DiseaseAmericanAutopsyBiological AssayBipolar DisorderBrainCandidate Disease GeneCell physiologyClustered Regularly Interspaced Short Palindromic RepeatsComplexDevelopmentDiagnosticDiseaseElectrophysiology (science)EngineeringEtiologyEvaluationExhibitsExonsFURIN geneFunctional disorderGene ExpressionGenesGeneticGenetic DiseasesGenetic EngineeringGenomicsGenotypeGlutamatesGoalsHeritabilityHumanImpairmentIn VitroIndividualInduced pluripotent stem cell derived neuronsIntronsLibrariesMachine LearningMapsMediatingMental disordersModelingModificationMolecularMutationNeuronsPathogenesisPathogenicityPathway interactionsPatientsPhenotypePost-Transcriptional RegulationProtein IsoformsProteinsQuantitative Trait LociRNARNA ProcessingRNA SplicingReporterResearchRiskRisk FactorsRoleSchizophreniaSingle Nucleotide PolymorphismSpliced GenesStructureSusceptibility GeneSynapsesTestingTranscriptional RegulationUntranslated RNAUntranslated RegionsVariantWorkautism spectrum disorderbasecausal variantcell typeclinical predictorscohortdisorder riskfallsfollow-upgenetic variantgenome wide association studygenome-wideimprovedin silicoinduced pluripotent stem cellinsightmachine learning methodmutantneuropsychiatric disorderneuropsychiatrynovelnovel therapeutic interventionoutcome predictionoverexpressionpersonalized approachpredictive modelingrisk variantstandard carestem cell biologystem cell modelsynaptic functiontherapeutic targettooltranscriptomics
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.
项目摘要
神经精神疾病(NPD),例如精神分裂症(SZ),自闭症谱系障碍(ASD)和双极性
疾病(BD)非常普遍,仅SZ就会影响近300万美国人。尽管有更多
比五十年的研究,对于这些疾病没有治疗,治疗标准仍然存在
不令人满意。全基因组关联研究(GWAS)表明,除了高度渗透稀有
突变,NPD风险还反映了数百种常见的单核苷酸多态性的影响
效应尺寸。该领域的一个主要挑战一直在照亮连接这些遗传变异的途径
(其中绝大多数属于非编码序列)靶向基因和因果细胞表型。到
了解这些无数风险的因果因果关系如何促进疾病风险,至关重要的是筛查推定的
因果变异并确定它们如何影响基因表达,已证明是细胞类型
具体以及细胞功能。最近出现的证据表明RNA有很大的贡献
包括SZ在内的许多复杂遗传疾病中的遗传力变化。基于我们的初步
分析和他人的工作,我们假设很大一部分NPD GWAS位点发挥了他们的作用
通过影响RNA对神经元功能的致病作用:其结构,修饰,蛋白质相互作用和
剪接。为了测试这一点,我们将应用新颖的工具和机器学习方法来预测和量化RNA剪接
在最大的SZ,ASD和BD GWAS中,以预测剪接定量性状基因座(SQTLS,AIM 1)。确认
对谷氨酸能和GABA能神经元中独立对外显子包容的真实影响(即主要细胞类型
在NPD中受到影响),多达数千个预测的剪接变体将通过大规模平行测试
记者分析,MAPSY(AIM 2)。最后,为了评估推定因果SQTL的细胞类型特异性影响
在AIM 1和2中确定了关于神经元成熟和突触功能的目标,我们将使用CRISPR基因编辑到
工程师在人类诱导的多能干细胞(HIPSC)的两个神经细胞模型中的这些突变
类型(AIM 3)。我们的总体目标是绘制和评估影响的NPD-GWAS基因座
替代剪接和神经元功能。我们的工作可能通过对角色的新见解来影响该领域
NPD病理生理学中常见变异的方法,可以为改善诊断的方法提供信息
临床轨迹,并开发新的治疗干预措施。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(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:
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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