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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

Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
Oxford Health NHS Foundation Trust, Oxford OX3 7JX, UK
GRIB, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain
Computational Sciences, Worldwide Research and Development, Pfizer Inc. 1 Portland St, Cambridge, MA 02139, USA
Neurosciences Therapeutic Area Unit, Glaxo Smith Kline R&D Ltd., Stevenage SG1 2NY, UK
Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8TA, UK
Members of the NIMA consortium, Cambridge, UK
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 425;
Received: 8 April 2019 / Revised: 29 April 2019 / Accepted: 1 May 2019 / Published: 8 May 2019
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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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. View Full-Text
Keywords: Alzheimer; JAK-STAT; multimodal; genomics; transcriptomics; animal models Alzheimer; JAK-STAT; multimodal; genomics; transcriptomics; animal models

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Nevado-Holgado, A.J.; Ribe, E.; Thei, L.; Furlong, L.; Mayer, M.-A.; Quan, J.; Richardson, J.C.; Cavanagh, J.; NIMA Consortium; Lovestone, S. Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development. Cells 2019, 8, 425.

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