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

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对遗传和环境信号作出反应，并最终有助于整个系统的健康和疾病状态。脱氧核糖核酸的水平因人而异。然而，目前尚不清楚dna水平的变化有多少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dna、遗传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人群，限制了对dna变异的理解。这是一个至关重要的知识缺口，因为世界各地不同人群在药物反应和疾病风险因素方面存在已知的遗传和环境差异，这可能归因于dna nam变异。评估不同人群中的DNAm变异，可以比较不同的遗传和环境暴露概况。确定所有人群共有的疾病途径将代表所有人类共有的健康和疾病机制。这样就可以确定对任何人群有效的药物靶点。识别限于特定遗传和/或环境暴露的疾病途径将反映对环境和遗传背景的适应。这将使我们能够确定支持我们在全球人群中观察到的疾病不一致的分子机制，并强调靶向治疗的机会。我们的第一个项目目标是绘制人类DNAm变异的遗传和环境决定因素，以了解DNAm变异的机制。我们将在全世界的人群中生成一个与dna相关的遗传目录。该目录将用于评估哪些已确定的与dna有关的遗传关联也与人类复杂性状有关。这是很重要的，因为这些发现可以告知表型相关遗传变异的功能作用，并最终-我们对人类表型变异机制的理解。该项目的第二个目标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的机制。该项目侧重于儿童和心脏代谢疾病，这些疾病在人群中存在重大的疾病差异和健康差异。例如，即使考虑到已知的遗传和环境风险因素，南亚血统的人患糖尿病的风险也要高得多。确定与2型糖尿病相关的DNAm变异是特定环境的，将有助于解释南亚人群中2型糖尿病风险过高的原因。在这样做的过程中，确定限于特定遗传和/或环境暴露概况的疾病途径，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合作伙伴关系的团队，汇集了从世界各地的个人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团队之间建立公平的伙伴关系。这对于建立研究遗传多样性数据集的能力和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 nam介导的健康和疾病的共同机制和特定环境机制具有重要的健康影响，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减少全球健康差距和不平等。

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.