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: 10626106
• 负责人: ROBERT A WATERLAND
• 金额: $ 56.21万
• 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/10626106
• 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 Factors; Role; Sampling; Social Justice; Spottings; Testing; Thyroid Gland; Tissue Sample; Tissues; United States National Institutes of Health; Validation; Variant; Weight; 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; risk prediction; 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.

项目摘要（摘要） 除了遗传学和环境外，表观遗传调节的个体差异可能决定 肥胖。在各种表观遗传机制中，DNA甲基化是最稳定的。一旦建立 开发，DNA甲基化模式在有线遗传上是可遗传的，并且可以在人类中持续多年。 然而，与遗传流行病学相比，研究肥胖的表观遗传决定剂更多 复杂，有两个主要原因。首先，表观遗传机制在很大程度上是细胞类型特异性的，因此研究 在易于获得的时机中（如外围血）中的DNA甲基化通常不提供信息 关于器官中对能量平衡很重要的表观遗传调节（如大脑）。第二，肥胖本身可以 影响DNA甲基化模式，因此“反向休闲”是一个问题。在过去的十年中，我们开创了 通过识别暴露全身性的人类基因组区域来规避这些障碍的方法 DNA甲基化的个体差异（全身间个体变异的相关区域 - corsivs）。去年，我们报告了近10,000张人类胸花的识别。这些地区稳定 和全身表观遗传变体 - 本质上是表观遗传学多态性 - 使大规模表观遗传学 使用外周血DNA的流行病学研究。我们的初始屏幕是在高加索人进行的，我们的 数据表明，还有更多的人类corsiv可以识别。鉴于非裔美国人都是 在基因组和表观基因组分析中的占代表性不足，而不成比例的负担不足 肥胖，现在迫切需要通过直接研究非裔美国人来扩展和多样化我们的胸花屏幕。 根据我们在该项目中的目标是1）在非裔美国人中执行辅助屏幕公正的屏幕 NIH基因组织表达计划（GTEX）中的供体，2）验证全身性个体表观遗传学 大量非裔美国人样本中基因表达的变异和跨组织预测，3）测试 AA儿童儿童肥胖症时出生预测时的辅助甲基化是否存在。我们预料到这一点 我们项目的完成将改变人类肥胖症的表观遗传学和表观遗传学的研究 一般来说。该项目对非裔美国人的重点是科学的，并且是从科学上讲是合理的。 社会正义。