Genetic and real-world clinical data, combined with empirical validation, nominate jak-stat signaling as a target for Alzheimer's disease therapeutic development

Mostra el registre complet Registre parcial de l'ítem

  • dc.contributor.author Nevado-Holgado, Alejo J.
  • dc.contributor.author Ribe, Elena
  • dc.contributor.author Thei, Laura
  • dc.contributor.author Furlong, Laura I., 1971-
  • dc.contributor.author Mayer, Miguel Ángel, 1960-
  • dc.contributor.author Quan, Jie
  • dc.contributor.author Richardson, Jill C.
  • dc.contributor.author Cavanagh, Jonathan
  • dc.contributor.author NIMA Consortium
  • dc.contributor.author Lovestone, Simon
  • dc.date.accessioned 2019-11-25T08:30:53Z
  • dc.date.available 2019-11-25T08:30:53Z
  • dc.date.issued 2019
  • dc.description.abstract 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.
  • dc.description.sponsorship This work was supported by the Wellcome Trust [104025], the European Union’s Horizon 2020 research and innovation programme 2014-2020 under Grant Agreement No 634143, the MRC Data Pathfinder award [MC_PC_17215], and the NIHR Oxford Health Biomedical Research Centre.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Nevado-Holgado AJ, Ribe E, Thei L, Furlong L, Mayer MA, Quan J. et al. 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 May 8;8(5). pii: E425. DOI 10.3390/cells8050425
  • dc.identifier.doi http://dx.doi.org/10.3390/cells8050425
  • dc.identifier.issn 2073-4409
  • dc.identifier.uri http://hdl.handle.net/10230/42949
  • dc.language.iso eng
  • dc.publisher MDPI
  • dc.relation.ispartof Cells. 2019 May 8;8(5)
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/634143
  • dc.rights © Nevado-Holgado AJ, Ribe E, Thei L, Furlong L, Mayer MA, Quan J. et al. 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/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Alzheimer
  • dc.subject.keyword JAK-STAT
  • dc.subject.keyword Animal models
  • dc.subject.keyword Genomics
  • dc.subject.keyword Multimodal
  • dc.subject.keyword Transcriptomics
  • dc.title Genetic and real-world clinical data, combined with empirical validation, nominate jak-stat signaling as a target for Alzheimer's disease therapeutic development
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Hospital del Mar Research Institute)
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)