Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements

Sparse profiling of CpG methylation in blood by microarrays have identified epigenetic links to common diseases. We apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal ~400), providing high-resolution methylation profiling (>1.3M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.EGA study EGAS00001003415

基于微阵列（microarrays）的血液CpG甲基化稀疏谱分析，已探明其与常见疾病的表观遗传关联。本研究针对约200例脂肪组织及匹配血液样本组成的临床队列（总样本量约400例），应用甲基化捕获测序（methylC-capture sequencing，MCC-Seq）技术，在调控元件（regulatory elements）上实现了超过130万个CpG位点的高分辨率甲基化谱分析。本研究通过关联循环血浆脂质水平，将甲基化特征与心血管代谢风险建立联系，并鉴定出在调控元件中具有独特定位模式的脂质相关CpG位点。通过与普通人群中约800例独立脂肪组织及血液样本的平行分析结果进行对比，本研究阐明了组织特异性与组织非特异性脂质关联调控区域的差异化特征。本研究还通过整合分析，对受（1）遗传调控及（2）表观遗传（环境）调控的脂肪组织特异性调控区域开展了后续验证。综上，对调控元件甲基化组的全面测序研究，揭示了一批同时在遗传与表观遗传层面与血浆脂质表型相关的功能变异的丰富调控图景。本研究的欧洲基因组学档案（EGA）研究编号为EGAS00001003415