鉴定与阿尔茨海默病相关的特定 APOE 转录本和功能元件。

Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease.

机构信息

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229, USA.

出版信息

Mol Neurodegener. 2024 Aug 29;19(1):63. doi: 10.1186/s13024-024-00751-7.

DOI:10.1186/s13024-024-00751-7

PMID:39210471

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11361112/

Abstract

BACKGROUND

The APOE gene is the strongest genetic risk factor for late-onset Alzheimer's Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized.

METHODS

To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development.

RESULTS

We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups.

CONCLUSION

The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.

摘要

背景

APOE 基因是导致晚期发病的阿尔茨海默病（LOAD）的最强遗传风险因素。然而，该基因座的基因调控机制仍不完全清楚。

方法

为了在 APOE 基因座内鉴定新的与 AD 相关的功能元件，我们整合了 SNP 变体与多组学数据，这些数据来自人类死后大脑，包括来自 3 个大脑区域和两个祖系（欧洲和非洲）的 2179 个 RNA-seq 样本、667 个 DNA 甲基化样本和 ChIP-seq 样本。此外，我们还绘制了人类大脑发育过程中 APOE 转录本的表达轨迹。

结果

我们发现了一种与 AD 相关的 APOE 转录本（jxn1.2.2），该转录本特别在背外侧前额叶皮层（DLPFC）中观察到。APOE jxn1.2.2 转录本与大脑神经病理学特征、认知障碍以及 DLPFC 中 APOE4 等位基因的存在有关。我们优先考虑了两个独立的功能 SNP（rs157580 和 rs439401），这些 SNP 与 jxn1.2.2 转录本丰度和 DNA 甲基化水平显著相关。这些 SNP 位于活性染色质区域内，影响与大脑相关的转录因子结合亲和力。这两个 SNP 在欧洲和非洲人群之间对 jxn1.2.2 转录本具有共同的影响。