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，在基因调节中起着核心作用。它有助于定义细胞对遗传和环境信号的反应，并最终有助于整个系统的健康和疾病状况。 dnam的水平因一个人而异。但是，目前尚不清楚DNAM水平的差异是由遗传或环境因素引起的，以及这种影响是否也与人类表型有关。了解DNAM，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后果至关重要。先前的研究仅限于欧洲血统的种群，将对DNAM变化的理解限制为有限的环境。这是一个至关重要的知识差距，因为在全球范围内，在整个人群中存在已知的遗传和环境差异和疾病危险因素，这可能归因于DNAM变异。各种人群群体中的DNAM变化允许在不同的遗传和环境暴露概况之间进行比较。所有人群常见的疾病途径的鉴定将代表所有人类常见的健康和疾病机制。这允许识别在任何人群中有效的药物靶标。仅限于特定遗传和/或环境暴露概况的疾病途径的鉴定将反映对环境和遗传环境的适应。这将允许鉴定我们在全球人群中观察到的疾病不一致的分子机制，并突出了有针对性治疗的机会。我们的第一个项目的目的是绘制人类DNAM变异的遗传和环境决定因素，以了解DNAM变异性的机制。我们将在全球范围内与DNAN的遗传关联目录。该目录将用于评估哪些确定的与DNAM的遗传关联也与人类复杂性状有关。 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跨种群。例如，即使考虑到已知的遗传和环境风险因素，南亚起源个人的糖尿病风险也大大较高。与2型糖尿病相关的DNAM变异的鉴定（特定于上下文）将有助于解释南亚人口组中多余的2型糖尿病风险。在此过程中，仅限于特定遗传和/或环境暴露概况的疾病途径的识别为有效的情况下靶向治疗或干预带来了机会。这项研究建立了全球团队的合作伙伴关系，以将全球个人收集的遗传和表观遗传数据汇总在一起。该提案的一个关键方面是在这些团队之间建立公平的伙伴关系。这对于在遗传多样的数据集中建立研究的能力是至关重要的，并提供有关对心脏代谢和儿童健康表型识别的国际相关研究，该研究对由DNAM介导的共同和环境特定的健康和疾病的特定机制具有很大的健康影响，因为它将促进通过针对性的干预措施或治疗来减少全球健康差异和能用措施。