Novel statistical methods for transcriptomic imputation to enhance understanding of causal mechanisms underlying human diseases

转录组插补的新统计方法可增强对人类疾病因果机制的理解

基本信息

  • 批准号:
    MR/V020749/1
  • 负责人:
  • 金额:
    $ 57.45万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

Genome-wide association studies (GWAS) have been successful in identifying chromosomal regions (loci) that contain genetic variants that contribute to many complex human traits and common diseases, including those that have major public health burden, such as cancers, diabetes and arthritis. Association signals for many complex traits predominantly localise to regions that influence disease by modulating gene expression (i.e. the process by which DNA is converted into a functional gene product), which may vary across tissues and cell types (referred to as the transcriptome). However, studies of the relationships between gene expression and complex traits have been restricted to investigations in small samples because of cost and availability of relevant tissues. Consequently, there has been limited progress in identifying the causal genes in GWAS regions and in understanding of the biological processes through which genetic variants impact on disease pathophysiology, thereby hindering the translation of these findings into the clinic through targeted drug development.One increasingly utilised approach to understand molecular pathways underlying human disease is through integrated analysis of genetic variation and transcriptomic data resources from large-scale tissue-based molecular profiling initiatives. For example, the Genotype-Tissue Expression Project has generated high-density genome-wide genotyping and gene expression across a wide range of tissues, and has made these data publicly available. One primary finding of these investigations has been the identification of expression quantitative trait loci (eQTL) that link genetic variation to the regulation of gene expression in diverse tissues. Methods have thus been developed that aim to detect association of complex traits with gene expression by: (i) building tissue-specific multi-eQTL models in these molecular profiling resources; and (ii) using these models to predict (or "impute") the transcriptome into GWAS data (based on individual-level genotypes or association summary statistics). However, existing transcriptome imputation methods typically: (i) consider each cell type separately, and do not take advantage of the observed correlations in gene expression between cell types driven by cross-tissue eQTLs; and/or (ii) do not account for eQTL model uncertainty (i.e. many different genetic variants may regulate gene expression), resulting in potential for false positive findings.The aim of this proposal is to develop novel statistical methods for transcriptomic imputation into GWAS to address these limitations by: (i) harnessing multi-tissue expression to build eQTL models that better predict gene expression than those that consider each cell type separately; and (ii) use computationally efficient Bayesian statistical methods that appropriately allow for uncertainty in the eQTL model, reducing the potential for "over-fitting". The methodology will be implemented in user friendly software that will be made freely available to the wider research community. The methodology and software will be utilised to create a repository of imputed multi-tissue gene expression into 500,000 participants from the UK Biobank for whom GWAS data are already available. These imputed transcriptomic profiles will be tested for association with rheumatoid arthritis and other musculoskeletal diseases, cardiovascular disease, cancer and diabetes, revealing novel causal genes and improving understanding of molecular mechanisms and relevant cell types underlying disease biology. The repository will also be returned to UK Biobank for archiving and distribution to approved researchers to identify causal genes for any trait of interest available in the resource. These analyses will have enhanced potential for translation of GWAS findings by identifying drug targets for up- or down-regulation of causal genes for which expression is associated with risk of disease.
全基因组关联研究(GWAS)已经成功地鉴定了含有遗传变异的染色体区域(基因座),这些遗传变异导致许多复杂的人类特征和常见疾病,包括那些具有重大公共卫生负担的疾病,如癌症,糖尿病和关节炎。许多复杂性状的关联信号主要定位于通过调节基因表达(即DNA转化为功能性基因产物的过程)影响疾病的区域,这可能在组织和细胞类型(称为转录组)之间存在差异。然而,基因表达和复杂性状之间的关系的研究一直局限于小样本的调查,因为成本和相关组织的可用性。因此,在鉴定GWAS区域中的致病基因和理解遗传变异影响疾病病理生理学的生物学过程方面进展有限,一种越来越多地用于理解人类疾病潜在分子途径的方法是通过遗传变异和转录组数据的综合分析资源从大规模的组织为基础的分子分析计划。例如,基因型-组织表达项目已经在广泛的组织中产生了高密度的全基因组基因分型和基因表达,并使这些数据公开可用。这些研究的一个主要发现是鉴定了表达数量性状基因座(eQTL),其将遗传变异与不同组织中的基因表达调控联系起来。因此,已经开发了旨在通过以下方式检测复杂性状与基因表达的关联的方法:(i)在这些分子谱分析资源中构建组织特异性多eQTL模型;以及(ii)使用这些模型来预测(或“估算”)转录组到GWAS数据中(基于个体水平的基因型或关联汇总统计)。然而,现有的转录组插补方法通常:(i)单独考虑每种细胞类型,并且不利用观察到的由跨组织eQTL驱动的细胞类型之间的基因表达的相关性;和/或(ii)不考虑eQTL模型的不确定性(即许多不同的遗传变异体可以调节基因表达),该提案的目的是开发新的统计方法,用于将转录组学插补到GWAS中,以通过以下方式解决这些局限性:(i)利用多组织表达来构建eQTL模型,该模型比单独考虑每种细胞类型的模型更好地预测基因表达;和(ii)使用适当考虑eQTL模型中的不确定性的计算有效的贝叶斯统计方法,从而降低了“过拟合”的可能性。该方法将在用户友好的软件中实施,该软件将免费提供给更广泛的研究界。该方法和软件将用于创建一个多组织基因表达的数据库,该数据库来自英国生物银行的50万名参与者,GWAS数据已经可用。将测试这些插补的转录组谱与类风湿性关节炎和其他肌肉骨骼疾病、心血管疾病、癌症和糖尿病的关联,揭示新的致病基因,并提高对疾病生物学基础的分子机制和相关细胞类型的理解。该储存库还将返回英国生物库存档和分发给批准的研究人员,以确定资源中任何感兴趣性状的因果基因。这些分析将通过确定上调或下调与疾病风险相关的致病基因的药物靶点,增强GWAS研究结果的翻译潜力。

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Andrew Morris其他文献

Creating sustainable innovation through design for behaviour change: full project report
通过行为改变设计创造可持续创新:完整的项目报告
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    K. Niedderer;J. MacKrill;S. Clune;Dan Lockton;Geke D. S. Ludden;Andrew Morris;R. Cain;E. Gardiner;Robin Gutteridge;M. Evans;P. Hekkert
  • 通讯作者:
    P. Hekkert
Evaluation of alternative intersection treatments at rural crossroads using simulation software
  • DOI:
    10.1080/15389588.2018.1528357
  • 发表时间:
    2018-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Sujanie Peiris;Bruce Corben;Michael Nieuwesteeg;Hampton C. Gabler;Andrew Morris;Diana Bowman;Michael G. Lenné;Michael Fitzharris
  • 通讯作者:
    Michael Fitzharris
How electric bikes reduce car use: A dual-mode ownership perspective
电动自行车如何减少汽车使用:一种双模式拥有视角
Advancing Hospital Acquired Pressure Injury Prevention with a Data-Driven Transdisciplinary Model
通过数据驱动的跨学科模型推进医院获得性压力性损伤的预防
  • DOI:
    10.1016/j.apmr.2025.03.025
  • 发表时间:
    2025-05-01
  • 期刊:
  • 影响因子:
    3.700
  • 作者:
    Bridget Fowler King;Colleen Johnson;Matthew Grissom;Andrew Morris;Miriam Rafferty
  • 通讯作者:
    Miriam Rafferty
Objective patient-related outcomes of rapid-response systems — a pilot study to demonstrate feasibility in two hospitals
  • DOI:
    10.1016/s1441-2772(23)02185-3
  • 发表时间:
    2013-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    Andrew Morris;Helen M. Owen;Karen Jones;Jillian Hartin;John Welch;Christian P. Subbe
  • 通讯作者:
    Christian P. Subbe

Andrew Morris的其他文献

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{{ truncateString('Andrew Morris', 18)}}的其他基金

Harnessing the power of diverse populations to empower clinical translation of genome-wide association studies of common human disease
利用不同人群的力量,促进人类常见疾病全基因组关联研究的临床转化
  • 批准号:
    MR/W029626/1
  • 财政年份:
    2023
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Research Grant
UKRI trusted and connected Data and Analytics Research Environments, Phase 1
UKRI 可信且互联的数据和分析研究环境,第一阶段
  • 批准号:
    MC_PC_21005
  • 财政年份:
    2021
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Intramural
Population Research UK Phase 1: Partnership Design & Dialogue
英国人口研究第一阶段:合作伙伴设计
  • 批准号:
    MC_PC_20024
  • 财政年份:
    2021
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Intramural
Phase 1 COVID-19 Data and Connectivity – National Core Study (Phase 1 D&C-NCS)
第 1 阶段 COVID-19 数据和连接 — 国家核心研究(第 1 阶段 D
  • 批准号:
    MC_PC_20058
  • 财政年份:
    2021
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Intramural
COVID-19: Data and Connectivity – National Core Study (D&C-NCS)
COVID-19:数据和连接 – 国家核心研究 (D
  • 批准号:
    MC_PC_20029
  • 财政年份:
    2020
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Intramural
Baskerville: a national accelerated compute resource
巴斯克维尔:国家加速计算资源
  • 批准号:
    EP/T022221/1
  • 财政年份:
    2020
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Research Grant
Open KE Fellowship: Translation of a Miniature CT-DO Sensor from the Laboratory to Real World Applications
开放 KE 奖学金:微型 CT-DO 传感器从实验室到现实世界应用的转化
  • 批准号:
    NE/S006451/2
  • 财政年份:
    2019
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Research Grant
UKRI ISCF DIH Programme Phase 3– Innovation Gateway, Health Data Research Hubs, and UK Health Data Research Alliance
UKRI ISCF DIH 计划第 3 阶段——创新网关、健康数据研究中心和英国健康数据研究联盟
  • 批准号:
    MC_PC_19002
  • 财政年份:
    2019
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Intramural
Open KE Fellowship: Translation of a Miniature CT-DO Sensor from the Laboratory to Real World Applications
开放 KE 奖学金:微型 CT-DO 传感器从实验室到现实世界应用的转化
  • 批准号:
    NE/S006451/1
  • 财政年份:
    2018
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Research Grant
Health Data Research UK - CORE Funds
英国健康数据研究 - CORE 基金
  • 批准号:
    HDR-CORE
  • 财政年份:
    2018
  • 资助金额:
    $ 57.45万
  • 项目类别:
    Intramural

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开发一种新颖的人体解剖学可视化、标签、通信和跟踪引擎。
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提高基因组学汇总统计效用的新方法
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急性脑静脉窦血栓形成患者的新风险分层评分
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A novel instrument for continuous blood pressure monitoring
一种新型连续血压监测仪器
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SCH:针对 AD/ADRD 大脑图像的新颖且可解释的统计学习
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