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

NIMA Consortium

doi:10.3390/cells8050425

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

NIMA Consortium

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29 Citations (Scopus)

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.

Original language	English
Article number	425
Journal	Cells
Volume	8
Issue number	5
DOIs	https://doi.org/10.3390/cells8050425
Publication status	Published - May 2019

Keywords

Alzheimer
Animal models
Genomics
JAK-STAT
Multimodal
Transcriptomics

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10.3390/cells8050425

Cite this

@article{352dd1b1eb5342a799586b1b36202ff8,

title = "Genetic and real-world clinical data, combined with empirical validation, nominate jak-stat signaling as a target for Alzheimer{\textquoteright}s disease therapeutic development",

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{\textquoteright}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.",

keywords = "Alzheimer, Animal models, Genomics, JAK-STAT, Multimodal, Transcriptomics",

author = "{NIMA Consortium} and Nevado-Holgado, {Alejo J.} and Elena Ribe and Laura Thei and Laura Furlong and Mayer, {Miguel Angel} and Jie Quan and Richardson, {Jill C.} and Jonathan Cavanagh and Simon Lovestone and Bullmore, {Edward T.} and Junaid Bhatti and Chamberlain, {Samuel J.} and Correia, {Marta M.} and Amber Dickinson and Andy Foster and Manfred Kitzbichler and Clare Knight and Lynall, {Mary Ellen} and Christina Maurice and Howard Mount and Ciara O{\textquoteright}Donnell and Pointon, {Linda J.} and Hyslop, {Peter St George} and Lorinda Turner and Barry Widmer and Williams, {Guy B.} and Morgan, {B. Paul} and Claire Leckey and Angharad Morgan and Caroline O{\textquoteright}Hagan and Samuel Touchard and Catherine Deith and John McClean and Alison McColl and Andrew McPherson and Paul Scouller and Murray Sutherland and Boddeke, {H. W.G.M.Erik} and Carmine Pariante and Diana Cash and Nicole Mariani and Maria Nettis and Naghmeh Nikkheslat and Hannah Sheridan and Federico Turkheimer and Loo, {Victoria Van} and Tobias Wood and Courtney Worrell and Zuzanna Zajkowska and Alison Baird",

note = "Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2019",

month = may,

doi = "10.3390/cells8050425",

language = "English",

volume = "8",

journal = "Cells",

issn = "2073-4409",

publisher = "MDPI",

number = "5",

}

TY - JOUR

T1 - Genetic and real-world clinical data, combined with empirical validation, nominate jak-stat signaling as a target for Alzheimer’s disease therapeutic development

AU - NIMA Consortium

AU - Nevado-Holgado, Alejo J.

AU - Ribe, Elena

AU - Thei, Laura

AU - Furlong, Laura

AU - Mayer, Miguel Angel

AU - Quan, Jie

AU - Richardson, Jill C.

AU - Cavanagh, Jonathan

AU - Lovestone, Simon

AU - Bullmore, Edward T.

AU - Bhatti, Junaid

AU - Chamberlain, Samuel J.

AU - Correia, Marta M.

AU - Dickinson, Amber

AU - Foster, Andy

AU - Kitzbichler, Manfred

AU - Knight, Clare

AU - Lynall, Mary Ellen

AU - Maurice, Christina

AU - Mount, Howard

AU - O’Donnell, Ciara

AU - Pointon, Linda J.

AU - Hyslop, Peter St George

AU - Turner, Lorinda

AU - Widmer, Barry

AU - Williams, Guy B.

AU - Morgan, B. Paul

AU - Leckey, Claire

AU - Morgan, Angharad

AU - O’Hagan, Caroline

AU - Touchard, Samuel

AU - Deith, Catherine

AU - McClean, John

AU - McColl, Alison

AU - McPherson, Andrew

AU - Scouller, Paul

AU - Sutherland, Murray

AU - Boddeke, H. W.G.M.Erik

AU - Pariante, Carmine

AU - Cash, Diana

AU - Mariani, Nicole

AU - Nettis, Maria

AU - Nikkheslat, Naghmeh

AU - Sheridan, Hannah

AU - Turkheimer, Federico

AU - Loo, Victoria Van

AU - Wood, Tobias

AU - Worrell, Courtney

AU - Zajkowska, Zuzanna

AU - Baird, Alison

PY - 2019/5

Y1 - 2019/5

N2 - 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.

AB - 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.

KW - Alzheimer

KW - Animal models

KW - Genomics

KW - JAK-STAT

KW - Multimodal

KW - Transcriptomics

UR - http://www.scopus.com/inward/record.url?scp=85081711793&partnerID=8YFLogxK

U2 - 10.3390/cells8050425

DO - 10.3390/cells8050425

M3 - Article

AN - SCOPUS:85081711793

SN - 2073-4409

VL - 8

JO - Cells

JF - Cells

IS - 5

M1 - 425

ER -

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

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Keywords

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