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Genetic and Real-World Clinical Data Combined with Empirical Validation Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development

机译:遗传和现实世界的临床数据结合经验验证提名Jak-Stat信号作为阿尔茨海默氏病治疗发展的目标

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摘要

As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer’s disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets.
机译:随着全基因组关联研究(GWAS)的规模不断扩大,与每种疾病相关的遗传变异数也相应增加。尽管每种疾病鉴定出的单核苷酸多态性(SNP)数量有所增加,但在许多情况下其生物学解释仍然难以捉摸。为了解决这个问题,我们将GWAS结果与正交的证据来源(即分子途径的当前知识)结合在一起。来自600万患者的真实临床数据;阿尔茨海默氏病(AD)患者组织中的RNA表达,以及用于实验验证的特制啮齿动物模型。更详细地说,首先我们显示,在途径水平上进行检查时,所有GWAS研究的分析均将AD分组为具有免疫性和炎症性疾病的簇。使用临床数据,我们显示这些疾病与AD的合并症程度与其在Janus激酶/信号转导子和转录激活子(JAK-STAT)途径中与分子参与者的遗传关联强度有关。然后,使用四个独立的RNA表达数据集,我们发现了AD中JAK-STAT通路基因改变的调控证据。最后,我们使用体外和体内啮齿动物模型来证明Aβ诱导该途径关键驱动基因的表达,提供实验证据来验证这些数据驱动的观察结果。因此,这些结果将JAK-STAT异常提名为AD中的主要病因事件,并因此成为治疗发展的潜在目标,而且证明了从头开始的多模式方法可从快速增长的基因组数据集中获取信息。

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