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A validated single-...
A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
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- Gawel, Danuta (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Serra-Musach, Jordi (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Lilja, Sandra (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Aagesen, Jesper (author)
- Reg Jonkoping Cty, Sweden
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- Arenas, Alex (author)
- Karolinska Institutet,Univ Rovira and Virgili, Spain
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- Asking, Bengt (author)
- Reg Jonkoping Cty, Sweden
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- Bengnér, Malin (author)
- Reg Jonkoping Cty, Sweden
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- Björkander, Janne (author)
- Reg Jonkoping Cty, Sweden
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- Biggs, Sophie (author)
- Linköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten
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- Ernerudh, Jan (author)
- Linköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten,Region Östergötland, Klinisk immunologi och transfusionsmedicin
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- Hjortswang, Henrik (author)
- Linköpings universitet,Medicinska fakulteten,Avdelningen för neuro- och inflammationsvetenskap,Region Östergötland, Magtarmmedicinska kliniken
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- Karlsson, Jan-Erik (author)
- Linköpings universitet,Avdelningen för kardiovaskulär medicin,Medicinska fakulteten,Reg Jonkoping Cty, Sweden
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- Köpsén, Mattias (author)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Jung Lee, Eun Jung (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Yonsei Univ, South Korea
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- Lentini, Antonio (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Li, Xinxiu (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Magnusson, Mattias (author)
- Linköpings universitet,Karolinska Institutet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten
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- Martinez, David (author)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Matussek, Andreas (author)
- Reg Jonkoping Cty, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden
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- Nestor, Colm (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Schäfer, Samuel (author)
- Linköpings universitet,Medicinska fakulteten,Avdelningen för barns och kvinnors hälsa
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- Seifert, Oliver (author)
- Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Reg Jonkoping Cty, Sweden
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- Sonmez, Ceylan (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten
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- Stjernman, Henrik (author)
- Reg Jonkoping Cty, Sweden
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- Tjärnberg, Andreas (author)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Wu, Simon (author)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Åkesson, Karin (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Reg Jonkoping Cty, Sweden
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- Shalek, Alex K. (author)
- MIT, MA 02139 USA; Broad Inst MIT and Harvard, MA 02142 USA; Ragon Inst MGH MIT and Harvard, MA USA
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- Stenmarker, Margaretha, 1960 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics,Reg Jonkoping Cty, Sweden; Inst Clin Sci, Sweden
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- Zhang, Huan (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Gustafsson, Mika (author)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Benson, Mikael (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus
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(creator_code:org_t)
- 2019-07-30
- 2019
- English.
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In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 11
- Related links:
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https://genomemedici...
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https://doi.org/10.1...
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http://urn.kb.se/res...
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https://liu.diva-por... (primary) (Raw object)
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
Close
- Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- Biomarker and drug discovery
- Network tools
- scRNA-seq
- Network tools; scRNA-seq; Biomarker and drug discovery
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
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Gawel, Danuta
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Serra-Musach, Jo ...
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Lilja, Sandra
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Aagesen, Jesper
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Arenas, Alex
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Asking, Bengt
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show more...
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Bengnér, Malin
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Björkander, Jann ...
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Biggs, Sophie
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Ernerudh, Jan
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Hjortswang, Henr ...
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Karlsson, Jan-Er ...
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Köpsén, Mattias
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Jung Lee, Eun Ju ...
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Lentini, Antonio
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Li, Xinxiu
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Magnusson, Matti ...
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Martinez, David
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Matussek, Andrea ...
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Nestor, Colm
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Schäfer, Samuel
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Seifert, Oliver
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Sonmez, Ceylan
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Stjernman, Henri ...
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Tjärnberg, Andre ...
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Wu, Simon
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Åkesson, Karin
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Shalek, Alex K.
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Stenmarker, Marg ...
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Zhang, Huan
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Gustafsson, Mika
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Benson, Mikael
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Genome Medicine
- By the university
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University of Gothenburg
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Karolinska Institutet
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Linköping University