Learning the Regulatory Code of Alzheimer's Disease Genomes
学习阿尔茨海默病基因组的调控密码
基本信息
- 批准号:10471969
- 负责人:
- 金额:$ 113.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinArchitectureAutopsyBase SequenceBiologicalBrainCell physiologyCellsChIP-seqChromatinClinical DataCodeComputer ModelsDNADNA SequenceDataData CollectionData SetDevelopmentDiseaseFamilyFrequenciesFutureGene ExpressionGenesGeneticGenetic RiskGenomeGenomicsGenotype-Tissue Expression ProjectGoalsHealth Care CostsHistonesHuman GeneticsImmuneIndividualInvestmentsLearningLifeLinkLinkage DisequilibriumMachine LearningMapsMedicalMeta-AnalysisMethodsMicrogliaModalityModelingMolecularMultiomic DataMutagenesisNeighborhoodsNeurodegenerative DisordersNucleic Acid Regulatory SequencesPathogenesisPathway interactionsPeripheralPersonal SatisfactionPersonsPopulationPost-Transcriptional RegulationQuantitative Trait LociRNARNA ProcessingRNA SplicingRegulationResearchSignal TransductionSingle Nucleotide PolymorphismStatistical ModelsSusceptibility GeneTechniquesTestingTherapeutic StudiesTrainingUntranslated RNAVacuumVariantWorkabeta accumulationcase controlcausal variantcell typedeep learningdeep learning modeldiverse dataendophenotypeepigenomicsexome sequencingfrontal lobefunctional genomicsgene networkgene regulatory networkgenetic analysisgenetic architecturegenetic variantgenome sequencinggenome wide association studygenome-widegenomic datain silicoinsertion/deletion mutationinsightlarge scale datamRNA Expressionmachine learning algorithmmachine learning methodmolecular phenotypemonocytemulti-ethnicnew therapeutic targetnovelnovel diagnosticsnovel therapeutic interventionnovel therapeuticsprotective alleleprotein aggregationrare variantrisk variantside effectsingle-cell RNA sequencingtherapeutic developmenttherapeutic targettooltraittranscriptometranscriptome sequencingtranscriptomicswhole genome
项目摘要
With ageing populations world-wide, neurodegenerative diseases are placing an ever increasing
burden on long- term well-being, healthcare costs and family life. Despite decades of research and
enormous investment, no disease-modifying treatment is available for the most common of these
diseases: Alzheimer’s (AD). The majority of these, to-date unsuccessful, efforts have focused
on one potential cause of AD: amyloid-β aggregation. Combining population-scale data
collection, human genetics and machine learning provides a way forward to uncover and characterize
new causal cellular processes involved in AD. This would provide an array of potential therapeutic
targets, increasing the chance that one will be more easily modulated than the amyloid-β pathway.
AD-specific genomic datasets of unprecedented scale are being actively collected: whole genome
sequencing (WGS) from ~20k individuals, gene expression (RNA-seq) and epigenomics (ATAC-seq,
histone ChIP-seq) from
>1000 post-mortem AD brains, single-cell transcriptomes and similar modalities in peripheral and
brain-resident innate immune cells (which we and others have shown to be AD-relevant). Effectively
integrating these diverse data to better understand AD represents a substantial computational
challenge, both in terms of data scale and analysis complexity. This proposal leverages
state-of-the-art deep learning (DL) and machine learning (ML), combined with human genetic
analyses, to address this challenge. We will train DL models to predict epigenomic signals and
RNA splicing from genomic sequence, enabling in silico mutagenesis to estimate the
functional impact (a “delta score”) of any genetic variant. The delta scores will be used in
genetic analyses that distinguish causal associations: cellular changes that drive AD
pathogenesis rather than downstream/side effects of disease. Delta scores will aid in
associating both rare and common variants to AD. To achieve sufficient power, rare variants must be
aggregated (e.g. for a gene): delta scores will allow filtering out many likely non-functional
(particularly non-coding) variants. Most common variants from AD Genome Wide Association Studies
(GWAS) are simply correlated with the causal variant due to linkage disequilibrium (LD). Delta
scores, combined with trans-ethnic GWAS, will enable estimation of the likely causal variant(s).
These analyses will highlight variants and genes involved in AD. However, genes do not operate in a
vacuum so robust probabilistic ML will be used to learn cell-type and disease-specific gene
regulatory networks from sorted bulk and single-cell RNA-seq. The detected networks will be
integrated with our genetic findings to discover network neighborhoods/pathways especially
enriched in AD variants. Such pathways will be prime candidates for future functional and
therapeutic studies of AD.
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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{{ truncateString('David Arthur Knowles', 18)}}的其他基金
Delineating the network effects of mental disorder-associated variants using convex optimization methods
使用凸优化方法描述精神障碍相关变异的网络效应
- 批准号:
10674871 - 财政年份:2022
- 资助金额:
$ 113.32万 - 项目类别:
Delineating the network effects of mental disorder-associated variants using convex optimization methods
使用凸优化方法描述精神障碍相关变异的网络效应
- 批准号:
10504516 - 财政年份:2022
- 资助金额:
$ 113.32万 - 项目类别:
A CRISPR/Cas13 approach for identifying individual transcript isoform function in cancer
用于识别癌症中个体转录亚型功能的 CRISPR/Cas13 方法
- 批准号:
10671680 - 财政年份:2022
- 资助金额:
$ 113.32万 - 项目类别:
Learning the Regulatory Code of Alzheimer's Disease Genomes
学习阿尔茨海默病基因组的调控密码
- 批准号:
10045386 - 财政年份:2020
- 资助金额:
$ 113.32万 - 项目类别:
Learning the Regulatory Code of Alzheimer's Disease Genomes
学习阿尔茨海默病基因组的调控密码
- 批准号:
10406760 - 财政年份:2020
- 资助金额:
$ 113.32万 - 项目类别:
Learning the Regulatory Code of Alzheimer's Disease Genomes
学习阿尔茨海默病基因组的调控密码
- 批准号:
10686319 - 财政年份:2020
- 资助金额:
$ 113.32万 - 项目类别:
Learning the Regulatory Code of Alzheimer's Disease Genomes
学习阿尔茨海默病基因组的调控密码
- 批准号:
10247588 - 财政年份:2020
- 资助金额:
$ 113.32万 - 项目类别:
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