Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer's Disease by Splicing-Based Aggregation.
Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer's Disease by Splicing-Based Aggregation.
复制标题
基于剪接的聚集对阿尔茨海默病TREM2外显子2低频遗传变异的选择性剪接调控。
DOI：
10.3390/ijms22189865
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发表时间：
2021-09-13
影响因子：
5.6
通讯作者：
Lee Y
中科院分区：
文献类型：
--
作者：
Han S;Na Y;Koh I;Nho K;Lee Y
TREM2 是最著名的阿尔茨海默病 (AD) 风险基因之一；然而，其 AD 相关变异的功能作用仍有待阐明，而且大多数已知的风险等位基因是低频变异，其研究具有挑战性。在这里，我们利用剪接引导的聚合方法，将多个低频 TREM2 变体捆绑在一起，以研究这些变体对 AD 中选择性剪接的功能影响。我们分析了两个独立队列中认知正常的老年对照（CN）和 AD 患者生成的全基因组测序（WGS）和 RNA-seq 数据，代表人脑额叶的三个区域：背外侧前额叶皮层（CN = 213 和 AD = 376）、额极（CN = 72 和 AD = 175）和下额叶（CN = 63 和 AD = 157）。我们在 TREM2 的第二个外显子中观察到外显子跳跃事件，在具有至少一个导致剪接调节元件功能丧失的低频变异的个体中，该外显子往往更频繁地跳跃（p = 0.0012）。此外，第二外显子高跳跃与低跳跃（即 TREM2 功能域缺失）的 AD 患者之间差异表达的基因在免疫相关通路中显着富集。因此，我们的剪接引导聚合方法为低频变异对 TREM2 第二外显子选择性剪接的调节提供了新的见解，并且可能成为进一步探索多种与疾病相关的低频变异的潜在分子机制的有用工具。
TREM2 is among the most well-known Alzheimer’s disease (AD) risk genes; however, the functional roles of its AD-associated variants remain to be elucidated, and most known risk alleles are low-frequency variants whose investigation is challenging. Here, we utilized a splicing-guided aggregation method in which multiple low-frequency TREM2 variants were bundled together to investigate the functional impact of those variants on alternative splicing in AD. We analyzed whole genome sequencing (WGS) and RNA-seq data generated from cognitively normal elderly controls (CN) and AD patients in two independent cohorts, representing three regions in the frontal lobe of the human brain: the dorsolateral prefrontal cortex (CN = 213 and AD = 376), frontal pole (CN = 72 and AD = 175), and inferior frontal (CN = 63 and AD = 157). We observed an exon skipping event in the second exon of TREM2, with that exon tending to be more frequently skipped (p = 0.0012) in individuals having at least one low-frequency variant that caused loss-of-function for a splicing regulatory element. In addition, genes differentially expressed between AD patients with high vs. low skipping of the second exon (i.e., loss of a TREM2 functional domain) were significantly enriched in immune-related pathways. Our splicing-guided aggregation method thus provides new insight into the regulation of alternative splicing of the second exon of TREM2 by low-frequency variants and could be a useful tool for further exploring the potential molecular mechanisms of multiple, disease-associated, low-frequency variants.