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

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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

David Arthur Knowles其他文献

David Arthur Knowles的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似国自然基金

时空序列驱动的神经形态视觉目标识别算法研究
  • 批准号:
    61906126
  • 批准年份:
    2019
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目
本体驱动的地址数据空间语义建模与地址匹配方法
  • 批准号:
    41901325
  • 批准年份:
    2019
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
  • 批准号:
    61802133
  • 批准年份:
    2018
  • 资助金额:
    23.0 万元
  • 项目类别:
    青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
  • 批准号:
    61872252
  • 批准年份:
    2018
  • 资助金额:
    64.0 万元
  • 项目类别:
    面上项目
针对内存攻击对象的内存安全防御技术研究
  • 批准号:
    61802432
  • 批准年份:
    2018
  • 资助金额:
    25.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Research Project 2
研究项目2
  • 批准号:
    10403256
  • 财政年份:
    2023
  • 资助金额:
    $ 113.32万
  • 项目类别:
Elucidating the Role of YAP and TAZ in the Aging Human Ovary
阐明 YAP 和 TAZ 在人类卵巢衰老中的作用
  • 批准号:
    10722368
  • 财政年份:
    2023
  • 资助金额:
    $ 113.32万
  • 项目类别:
Multi-omic phenotyping of human transcriptional regulators
人类转录调节因子的多组学表型分析
  • 批准号:
    10733155
  • 财政年份:
    2023
  • 资助金额:
    $ 113.32万
  • 项目类别:
Gene regulatory networks in early lung epithelial cell fate decisions
早期肺上皮细胞命运决定中的基因调控网络
  • 批准号:
    10587615
  • 财政年份:
    2023
  • 资助金额:
    $ 113.32万
  • 项目类别:
Defining mechanisms of metabolic-epigenetic crosstalk that drive glioma initiation
定义驱动神经胶质瘤发生的代谢-表观遗传串扰机制
  • 批准号:
    10581192
  • 财政年份:
    2023
  • 资助金额:
    $ 113.32万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了