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

项目概要（摘要） 除了遗传和环境外，表观遗传调节中的个体间变异可能决定了 肥胖在各种表观遗传机制中，DNA甲基化是最稳定的;一旦在 在发育过程中，DNA甲基化模式是有丝分裂可遗传的，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因素要多得多。 复杂，主要有两个原因。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 容易获得的组织（如外周血）中的DNA甲基化通常不能提供信息 关于对能量平衡很重要的器官（如大脑）的表观遗传调节。其次，肥胖本身可以 影响DNA甲基化模式，因此“反向因果关系”是一个问题。在过去的十年里，我们开创了一个 一种通过鉴定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（系统性个体间变异的相关区域- CoRSIV）。去年，我们报告了近10，000例人类CoRSIV的鉴定。这些地区是稳定的 和系统性表观遗传变异-基本上是表观遗传多态性-使大规模的表观遗传 使用外周血DNA的流行病学研究。我们的初步筛选是在高加索人中进行的， 数据显示还有更多的人类CoRSIV需要鉴定。考虑到非洲裔美国人既是 在基因组和表观基因组分析中的代表性严重不足， 肥胖，现在迫切需要通过直接研究非裔美国人来扩大和多样化我们的CoRSIV筛查。 因此，我们在这个项目中的目标是1）在非洲裔美国人中对CoRSIV进行无偏见的筛选 NIH基因-组织表达计划（GTEx）中的供体，2）全身个体间表观遗传学 大样本非裔美国人中基因表达的变异和跨组织预测，以及3）测试 出生时CoRSIV甲基化是否可预测AA儿童的儿童期肥胖风险我们预计 我们项目的完成将改变人类肥胖的表观遗传学研究，以及表观遗传流行病学。 梗概.该项目对非裔美国人的关注是合理的，无论是科学上还是从基础上， 社会正义

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.