在大量人脑组织样本中，对与 AD 神经病理学相关的假定表观遗传改变的 EWAS 位点进行精细映射和复制。
Fine-mapping and replication of EWAS loci harboring putative epigenetic alterations associated with AD neuropathology in a large collection of human brain tissue samples.
机构信息
Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA.
Rush Alzheimer's Disease Center & Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
出版信息
Alzheimers Dement. 2023 Apr;19(4):1216-1226. doi: 10.1002/alz.12761. Epub 2022 Aug 12.
INTRODUCTION
Our previous epigenome-wide association study (EWAS) of Alzheimer's disease (AD) in human brain identified 71 CpGs associated with AD pathology. However, due to low coverage of the Illumina platform, many important CpGs might have been missed.
METHODS
In a large collection of human brain tissue samples (N = 864), we fine-mapped previous EWAS loci by targeted bisulfite sequencing and examined their associations with AD neuropathology. DNA methylation was also linked to gene expression of the same brain cortex.
RESULTS
Our targeted sequencing captured 130 CpGs (∼1.2 kb), 93 of which are novel. Of the 130 CpGs, 57 sites (only 17 included in previous EWAS) and 12 gene regions (e.g., ANK1, BIN1, RHBDF2, SPG7, PODXL) were significantly associated with amyloid load. DNA methylation in some regions was associated with expression of nearby genes.
DISCUSSION
Targeted methylation sequencing can validate previous EWAS loci and discover novel CpGs associated with AD pathology.
简介
我们之前对人类大脑中的阿尔茨海默病（AD）进行的全基因组关联研究（EWAS）发现了 71 个与 AD 病理相关的 CpG。然而，由于 Illumina 平台的覆盖范围较低，许多重要的 CpG 可能已经被遗漏。
方法
在大量的人类脑组织样本（N=864）中，我们通过靶向亚硫酸氢盐测序对先前的 EWAS 位点进行精细映射，并检查它们与 AD 神经病理学的关联。还将 DNA 甲基化与相同大脑皮层的基因表达联系起来。
结果
我们的靶向测序捕获了 130 个 CpG（约 1.2kb），其中 93 个是新的。在这 130 个 CpG 中，有 57 个位点（仅包括先前 EWAS 中的 17 个）和 12 个基因区域（例如，ANK1、BIN1、RHBDF2、SPG7、PODXL）与淀粉样蛋白负荷显著相关。一些区域的 DNA 甲基化与附近基因的表达有关。
讨论
靶向甲基化测序可以验证先前的 EWAS 位点并发现与 AD 病理相关的新 CpG。
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