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

中文翻译：

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鉴定与阿尔茨海默病相关的特定 APOE 转录本和功能元件


APOE 基因是晚发性阿尔茨海默病 （LOAD） 的最强遗传风险因素。然而，该基因座的基因调控机制仍未完全表征。为了鉴定 APOE 基因座中与 AD 相关的新功能元件，我们将 SNP 变体与来自人类死后大脑的多组学数据相结合，包括来自 3 个大脑区域和两个祖先 （欧洲和非洲） 的 2,179 个 RNA-seq 样本、667 个 DNA 甲基化样本和 ChIP-seq 样本。此外，我们还绘制了发育过程中 APOE 转录本在人脑中的表达轨迹。我们确定了一种 AD 连锁的 APOE 转录本 （jxn1.2.2），特别是在背外侧前额叶皮层 （DLPFC） 中观察到。APOE jxn1.2.2 转录本与脑神经病理学特征、认知障碍和 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性 SNP （rs157580 和 rs439401），它们与 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，影响脑相关转录因子结合亲和力。这两个 SNP 对欧洲和非洲种族群体之间的 jxn1.2.2 转录本具有共同影响。新型 APOE 功能元件为潜在的治疗靶点提供了对疾病病因的机制见解。