Harnessing DNA methylation variation between populations to understand disease discordance across ancestries

利用人群之间的 DNA 甲基化变异来了解不同祖先的疾病差异

• 批准号: MR/X021599/1
• 负责人: Josine Min
• 金额: $ 270.87万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021599%2F1
• 关键词: Harnessing; DNA; methylation; variation; between

DNA methylation (DNAm) is an epigenetic mechanism that plays a central role in gene regulation. It helps to define how cells respond to genetic and environmental signals and, ultimately, contributes to whole system health and disease status. Levels of DNAm differ from one person to another. However, it is unclear how much of the variation in DNAm levels is caused by genetic or environmental factors and if such effects also relate to human phenotypes. Understanding the relationships between DNAm, genetics and environment is essential for both understanding pathways of health and disease and disease consequences. Prior research has been limited to populations of European ancestry, restricting understanding of DNAm variation to limited contexts. This is a crucial knowledge gap because there are known genetic and environmental differences in drug response and disease risk factors across population groups worldwide which may be attributable to DNAm variation.Evaluating DNAm variation in diverse population groups allows comparison across varying genetic and environmental exposure profiles. Identification of disease pathways common to all populations will represent mechanisms of health and disease that are common across all humans. This allows identification of drug targets that will be effective in any population group. Identification of disease pathways restricted to specific genetic and/or environmental exposure profile will reflect adaptation to environmental and genetic context. This will allow identification of molecular mechanisms that underpin the disease discordance that we observe across global populations and highlight opportunities for targeted treatments. Our first project aim is to map genetic and environmental determinants of human DNAm variation to understand mechanisms of DNAm variability. We will generate a catalog of genetic associations with DNAm across populations worldwide. This catalog will be used to assess which of the identified genetic associations with DNAm are also associated with human complex traits. This is important because the findings can inform the functional role of phenotype-associated genetic variation, and ultimately - our understanding of the mechanisms underlying human phenotype variation.The second aim of the project is to understand mechanisms of disease and disease discordance observed between population groups for childhood and cardiometabolic disease related phenotypes.This project focusses on childhood and cardiometabolic disease for which there is substantial disease discordance and health disparity across populations. For example, diabetes risk is substantially higher in individuals of South Asian origin even after accounting for known genetic and environmental risk factors. Identification of DNAm variation associated with type 2 diabetes that is context specific will contribute to explaining excess type 2 diabetes risk in the South Asian population group. In doing so, Identification of disease pathways restricted to specific genetic and/or environmental exposure profiles brings the opportunity to target treatment or intervention where it is effective. This research builds a global partnership of teams to bring together genetic and epigenetic data collected from individuals worldwide. A key aspect of this proposal is building equitable partnerships between these teams. This is essential in order to build capacity for research in genetically diverse datasets and to provide internationally relevant research on cardiometabolic and child health phenotypesIdentification of common and context specific mechanisms of health and disease mediated by DNAm is of high health impact because it will enable actions to reduce global health disparity and inequity via targeted interventions or treatments.

DNA甲基化（DNAm）是一种表观遗传机制，在基因调控中起着核心作用。它有助于确定细胞如何响应遗传和环境信号，并最终有助于整个系统的健康和疾病状态。DNAm的水平因人而异。然而，目前还不清楚DNA m水平的变化有多少是由遗传或环境因素引起的，以及这些影响是否也与人类表型有关。了解DNA、遗传学和环境之间的关系对于了解健康和疾病的途径以及疾病的后果至关重要。先前的研究仅限于欧洲血统的人群，限制了对DNA变异的理解。这是一个关键的知识差距，因为有已知的遗传和环境差异的药物反应和疾病的风险因素，在世界各地的人口群体，这可能是由于DNAm的变化。评估DNAm的变化，在不同的人口群体可以比较不同的遗传和环境暴露概况。确定所有人群共同的疾病途径将代表所有人类共同的健康和疾病机制。这允许识别将在任何人群中有效的药物靶点。确定限于特定遗传和/或环境暴露概况的疾病途径将反映对环境和遗传背景的适应。这将有助于确定我们在全球人群中观察到的疾病不一致性的分子机制，并突出靶向治疗的机会。我们的第一个项目的目的是映射人类DNAm变异的遗传和环境决定因素，以了解DNAm变异的机制。我们将生成一个全球人群中与DNAm遗传相关的目录。该目录将用于评估与DNAm的已鉴定遗传关联中的哪些也与人类复杂性状相关。这一点很重要，因为这些发现可以为表型相关遗传变异的功能作用提供信息，最终-我们对人类表型变异机制的理解。该项目的第二个目的是了解儿童和心脏代谢疾病相关表型人群之间观察到的疾病和疾病不一致性的机制。该项目侧重于儿童和心脏代谢疾病，人口之间的疾病不一致和健康差距。例如，即使在考虑了已知的遗传和环境风险因素后，南亚血统的个体患糖尿病的风险也要高得多。识别与2型糖尿病相关的DNAm变异，这是特定的背景将有助于解释南亚人群中2型糖尿病的风险过高。在此过程中，确定疾病途径仅限于特定的遗传和/或环境暴露概况，这为有效的靶向治疗或干预提供了机会。这项研究建立了一个全球团队合作伙伴关系，汇集了从世界各地收集的遗传和表观遗传数据。这项建议的一个关键方面是在这些小组之间建立公平的伙伴关系。这对于建立在遗传多样性数据集上进行研究的能力以及提供关于心脏代谢和儿童健康表型的国际相关研究至关重要。确定由DNA介导的健康和疾病的共同和特定背景机制具有很高的健康影响，因为它将使人们能够采取行动，通过有针对性的干预或治疗来减少全球健康差距和不公平。