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: 10272655
• 负责人: ROBERT A WATERLAND
• 金额: $ 51.96万
• 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/10272655
• 关键词: Adipocytes; Affect; African; African American; Age; Archives; Area; Asians; 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; Minority Groups; 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; 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）