Deep post-GWAS analysis identifies potential risk genes and risk variants for Alzheimer's disease, providing new insights into its disease mechanisms.
Deep post-GWAS analysis identifies potential risk genes and risk variants for Alzheimer's disease, providing new insights into its disease mechanisms.
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DOI：
10.1038/s41598-021-99352-3
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发表时间：
2021-10-15
影响因子：
4.6
通讯作者：
Zhang ZD
中科院分区：
文献类型：
--
作者：
Wang Z;Zhang Q;Lin JR;Jabalameli MR;Mitra J;Nguyen N;Zhang ZD
阿尔茨海默病（Alzheimer's disease，AD）是一种遗传复杂的多因素神经退行性疾病。它影响全球超过4500万人，目前仍无法治疗。尽管全基因组关联研究（GWAS）已经确定了许多AD相关的常见变异，但目前已知只有约25个基因影响AD的发生风险，尽管其具有高度多基因性。此外，GWAS AD相关信号的潜在风险变量仍然未知。在这里，我们描述了一个深入的后GWAS分析AD相关的变异，使用一个集成的计算框架来预测疾病基因及其风险变异。我们在203个风险区域中确定了342个推定的AD风险基因，涵盖502个AD相关的常见变异。GWAS目录中收集的246个AD风险基因尚未被GWAS确定为AD风险基因，342个AD风险基因中有115个在风险区域之外，可能受到其中包含的转录调控元件的调控。更重要的是，对于109个AD风险基因，我们预测了150个编码和调节（启动子或增强子）类型的风险变体，其中85个（57%）得到了功能注释的支持。深入的功能分析表明，AD风险基因在AD相关通路或GO术语中过度表达-例如，补体和凝血级联反应以及免疫应答的磷酸化和激活，并且它们的表达相对富集于人脑的小胶质细胞、内皮细胞和周细胞。我们发现了9个AD风险基因，例如，IL 1 RAP、PMAIP 1、LAMTOR 4-作为AD生存预后的预测因子，以及ARL 6 IP 5等基因在AD患者和参与AD进展的正常个体之间具有改变的网络连接。我们的发现为开发针对AD风险基因或风险变体的治疗方法以影响AD发病机制开辟了新策略。
Alzheimer’s disease (AD) is a genetically complex, multifactorial neurodegenerative disease. It affects more than 45 million people worldwide and currently remains untreatable. Although genome-wide association studies (GWAS) have identified many AD-associated common variants, only about 25 genes are currently known to affect the risk of developing AD, despite its highly polygenic nature. Moreover, the risk variants underlying GWAS AD-association signals remain unknown. Here, we describe a deep post-GWAS analysis of AD-associated variants, using an integrated computational framework for predicting both disease genes and their risk variants. We identified 342 putative AD risk genes in 203 risk regions spanning 502 AD-associated common variants. 246 AD risk genes have not been identified as AD risk genes by previous GWAS collected in GWAS catalogs, and 115 of 342 AD risk genes are outside the risk regions, likely under the regulation of transcriptional regulatory elements contained therein. Even more significantly, for 109 AD risk genes, we predicted 150 risk variants, of both coding and regulatory (in promoters or enhancers) types, and 85 (57%) of them are supported by functional annotation. In-depth functional analyses showed that AD risk genes were overrepresented in AD-related pathways or GO terms—e.g., the complement and coagulation cascade and phosphorylation and activation of immune response—and their expression was relatively enriched in microglia, endothelia, and pericytes of the human brain. We found nine AD risk genes—e.g., IL1RAP, PMAIP1, LAMTOR4—as predictors for the prognosis of AD survival and genes such as ARL6IP5 with altered network connectivity between AD patients and normal individuals involved in AD progression. Our findings open new strategies for developing therapeutics targeting AD risk genes or risk variants to influence AD pathogenesis.
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影响因子：
3.6
作者：
Bencze J;Mórotz GM;Seo W;Bencs V;Kálmán J;Miller CCJ;Hortobágyi T
通讯作者：
Hortobágyi T
影响因子：
4.8
作者：
Funmilayo, Eniola;Yeates, Aduke;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina
DOI：
10.1073/pnas.1507125112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Darmanis S;Sloan SA;Zhang Y;Enge M;Caneda C;Shuer LM;Hayden Gephart MG;Barres BA;Quake SR
通讯作者：
Quake SR
DOI：
10.1073/pnas.0503689102
发表时间：
2005-09-20
影响因子：
11.1
作者：
Andersen, OM;Reiche, J;Willnow, TE
通讯作者：
Willnow, TE
影响因子：
4.2
作者：
Hashimoto, Y;Nawa, M;Matsuoka, M
通讯作者：
Matsuoka, M