Systemic interindividual epigenetic variants in African Americans: Identification, characterization, and prospective associations with obesity

非裔美国人的系统性个体间表观遗传变异：鉴定、表征以及与肥胖的前瞻性关联

• 批准号: 10473790
• 负责人: ROBERT A WATERLAND
• 金额: $ 58.14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473790
• 关键词: Adipocytes; Affect; African; African American; African American population; African ancestry; Age; Archives; Area; Asian population; Birth; Blood; Body mass index; Brain; California; Caucasians; Child; Childhood; Cohort Studies; Consent; Cross-Sectional Studies; Custom; DNA; DNA Methylation; Data; Databases; Development; Ectoderm; Embryo; Endoderm; Environment; Epidemiology; Epigenetic Process; Etiology; Exhibits; Eye diseases; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomic DNA; Genomic Segment; Genomics; Germ Layers; Heart; Heritability; Human; Hypothalamic structure; Individual; Individuality; Los Angeles; Maps; Measurement; Measures; Mediating; Mesoderm; Metabolic Diseases; Methylation; Mitotic; Nature; Neurons; Newborn Infant; Obesity; Organ; Overweight; Paper; Participant; Population; Prospective Studies; Public Health; Publishing; Reporting; Risk; Risk Factors; Role; Sampling; Social Justice; Testing; Thyroid Gland; Time; Tissue Sample; Tissues; United States National Institutes of Health; Validation; Variant; Weight; base; bisulfite sequencing; cell type; computational pipelines; energy balance; epidemiology study; epigenetic regulation; epigenetic variation; epigenomics; genetic epidemiology; genome sequencing; genome-wide; inter-individual variation; methylation pattern; multi-ethnic; novel; obesity in children; obesity prevention; obesity risk; peripheral blood; programs; prospective; racial minority population; scale up; screening; transcriptome sequencing; whole genome

PROJECT SUMMARY (Abstract) In addition to genetics and environment, interindividual variation in epigenetic regulation may determine risk of obesity. Of various epigenetic mechanisms, DNA methylation is this most stable; once established during development, DNA methylation patterns are mitotically heritable and can persist for many years in humans. Compared to genetic epidemiology, however, studying epigenetic determinants of obesity is much more complicated, for two main reasons. First, epigenetic mechanisms are largely cell type-specific, so studying DNA methylation in easily accessible tissues (like peripheral blood) does not generally provide information about epigenetic regulation in organs important to energy balance (like the brain). Second, obesity itself can affect DNA methylation patterns, so `reverse causality' is a problem. Over the last decade we pioneered an approach to circumvent these obstacles by identifying human genomic regions that exhibit systemic interindividual variation in DNA methylation (correlated regions of systemic interindividual variation – CoRSIVs). Last year we reported the identification of nearly 10,000 human CoRSIVs. These regions are stable and systemic epigenetic variants – essentially epigenetic polymorphisms - enabling large-scale epigenetic epidemiologic studies using peripheral blood DNA. Our initial screen was conducted in Caucasians, and our data show that there are many more human CoRSIVs to identify. Given that African Americans are both grossly underrepresented in genomic and epigenomic analyses, and disproportionately overburdened by obesity, it is now urgent to scale up and diversify our CoRSIV screen by studying African Americans directly. Accordingly, our Aims in this project are to 1) Perform an unbiased screen for CoRSIVs in African American donors in the NIH Gene-Tissue Expression program (GTEx), 2) Validate systemic interindividual epigenetic variation and cross-tissue prediction of gene expression in a large sample of African Americans, and 3) Test whether CoRSIV methylation at birth predicts risk of childhood obesity in AA children. We anticipate that completion of our project will transform the study of epigenetics in human obesity, and epigenetic epidemiology in general. The focus of this project on African Americans is justified both scientifically and from the basis of social justice.

项目概要（摘要） 除了遗传和环境之外，表观遗传调控的个体差异也可能决定患病风险。 在各种表观遗传机制中，DNA 甲基化一旦建立，是最稳定的。 在发育过程中，DNA甲基化模式具有有丝分裂遗传性，并且可以在人类体内持续多年。 然而，与遗传流行病学相比，研究肥胖的表观遗传决定因素要多得多。 复杂，主要有两个原因，首先，表观遗传机制很大程度上是细胞类型特异性的，因此需要研究。 易于接近的组织（如外周血）中的 DNA 甲基化通常不能提供信息 其次，肥胖本身可以影响能量平衡的重要器官（如大脑）的表观遗传调控。 影响 DNA 甲基化模式，因此“反向因果关系”是一个问题。在过去的十年中，我们开创了一个新的解决方案。 通过识别表现出系统性的人类基因组区域来规避这些障碍的方法 DNA 甲基化的个体间变异（系统个体间变异的相关区域 – 去年，我们报告了近 10,000 种人类 CoRSIV 的鉴定，这些区域是稳定的。 和系统性表观遗传变异——本质上是表观遗传多态性——实现大规模表观遗传 我们使用外周血 DNA 进行了流行病学研究。 数据显示，鉴于非裔美国人都是冠状病毒，还有更多的人类冠状病毒有待识别。 在基因组和表观基因组分析中的代表性严重不足，并且负担过重 由于肥胖，现在迫切需要通过直接研究非裔美国人来扩大我们的 CoRSIV 筛查规模并使其多样化。 因此，我们此项目的目标是 1) 对非裔美国人的 CoRSIV 进行公正的筛查 NIH 基因组织表达计划 (GTEx) 的捐赠者，2) 验证系统性个体间表观遗传 非裔美国人大样本中基因表达的变异和跨组织预测，以及 3) 测试 出生时 CoRSIV 甲基化是否可以预测 AA 儿童的儿童期肥胖风险。 我们项目的完成将改变人类肥胖表观遗传学和表观遗传学流行病学的研究 总的来说，该项目对非裔美国人的关注在科学上和基础上都是合理的。 社会正义。