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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

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...

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Autores principales: Nevado-Holgado, Alejo J., Ribe, Elena, Thei, Laura, Furlong, Laura, Mayer, Miguel-Angel, Quan, Jie, Richardson, Jill C., Cavanagh, Jonathan, Lovestone, Simon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562942/
https://www.ncbi.nlm.nih.gov/pubmed/31072055
http://dx.doi.org/10.3390/cells8050425
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author Nevado-Holgado, Alejo J.
Ribe, Elena
Thei, Laura
Furlong, Laura
Mayer, Miguel-Angel
Quan, Jie
Richardson, Jill C.
Cavanagh, Jonathan
Lovestone, Simon
author_facet Nevado-Holgado, Alejo J.
Ribe, Elena
Thei, Laura
Furlong, Laura
Mayer, Miguel-Angel
Quan, Jie
Richardson, Jill C.
Cavanagh, Jonathan
Lovestone, Simon
author_sort Nevado-Holgado, Alejo J.
collection PubMed
description 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.
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spelling pubmed-65629422019-06-17 Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development Nevado-Holgado, Alejo J. Ribe, Elena Thei, Laura Furlong, Laura Mayer, Miguel-Angel Quan, Jie Richardson, Jill C. Cavanagh, Jonathan Lovestone, Simon Cells Article 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. MDPI 2019-05-08 /pmc/articles/PMC6562942/ /pubmed/31072055 http://dx.doi.org/10.3390/cells8050425 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nevado-Holgado, Alejo J.
Ribe, Elena
Thei, Laura
Furlong, Laura
Mayer, Miguel-Angel
Quan, Jie
Richardson, Jill C.
Cavanagh, Jonathan
Lovestone, Simon
Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
title Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
title_full Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
title_fullStr Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
title_full_unstemmed Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
title_short Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
title_sort genetic and real-world clinical data, combined with empirical validation, nominate jak-stat signaling as a target for alzheimer’s disease therapeutic development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562942/
https://www.ncbi.nlm.nih.gov/pubmed/31072055
http://dx.doi.org/10.3390/cells8050425
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