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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-05-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/8/5/425 |
| _version_ | 1827853543157006336 |
|---|---|
| author | Alejo J. Nevado-Holgado Elena Ribe Laura Thei Laura Furlong Miguel-Angel Mayer Jie Quan Jill C. Richardson Jonathan Cavanagh NIMA Consortium Simon Lovestone |
| author_facet | Alejo J. Nevado-Holgado Elena Ribe Laura Thei Laura Furlong Miguel-Angel Mayer Jie Quan Jill C. Richardson Jonathan Cavanagh NIMA Consortium Simon Lovestone |
| author_sort | Alejo J. Nevado-Holgado |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T11:08:16Z |
| format | Article |
| id | doaj.art-1c6cbd8040974f6f8cd58b565d2beff8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T11:08:16Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-1c6cbd8040974f6f8cd58b565d2beff82023-09-02T03:26:11ZengMDPI AGCells2073-44092019-05-018542510.3390/cells8050425cells8050425Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic DevelopmentAlejo J. Nevado-Holgado0Elena Ribe1Laura Thei2Laura Furlong3Miguel-Angel Mayer4Jie Quan5Jill C. Richardson6Jonathan Cavanagh7NIMA Consortium8Simon Lovestone9Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UKDepartment of Psychiatry, University of Oxford, Oxford OX3 7JX, UKDepartment of Psychiatry, University of Oxford, Oxford OX3 7JX, UKGRIB, Hospital del Mar Medical Research Institute, 08003 Barcelona, SpainGRIB, Hospital del Mar Medical Research Institute, 08003 Barcelona, SpainComputational Sciences, Worldwide Research and Development, Pfizer Inc. 1 Portland St, Cambridge, MA 02139, USANeurosciences Therapeutic Area Unit, Glaxo Smith Kline R&D Ltd., Stevenage SG1 2NY, UKInstitute of Health and Wellbeing, University of Glasgow, Glasgow G12 8TA, UKMembers of the NIMA consortium, Cambridge, UKDepartment of Psychiatry, University of Oxford, Oxford OX3 7JX, UKAs 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.https://www.mdpi.com/2073-4409/8/5/425AlzheimerJAK-STATmultimodalgenomicstranscriptomicsanimal models |
| spellingShingle | Alejo J. Nevado-Holgado Elena Ribe Laura Thei Laura Furlong Miguel-Angel Mayer Jie Quan Jill C. Richardson Jonathan Cavanagh NIMA Consortium Simon Lovestone Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development Cells Alzheimer JAK-STAT multimodal genomics transcriptomics animal models |
| 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 | Alzheimer JAK-STAT multimodal genomics transcriptomics animal models |
| url | https://www.mdpi.com/2073-4409/8/5/425 |
| work_keys_str_mv | AT alejojnevadoholgado geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT elenaribe geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT laurathei geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT laurafurlong geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT miguelangelmayer geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT jiequan geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT jillcrichardson geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT jonathancavanagh geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT nimaconsortium geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment AT simonlovestone geneticandrealworldclinicaldatacombinedwithempiricalvalidationnominatejakstatsignalingasatargetforalzheimersdiseasetherapeuticdevelopment |