A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes
Open accessAbstract
Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were systematically mapped to tissues they affect from disease-relevant literature in PubMed to create a disease–tissue covariation matrix of high-confidence associations of >1,000 diseases to 73 tissues. By retrieving >2,000 known disease genes, and generating 1,500 disease-associated protein complexes, we analyzed the differential expression of a gene or complex involved in a particular disease in the tissues affected by the disease, compared with nonaffected tissues. When this analysis is scaled to all diseases in our dataset, there is a significant tendency for disease genes and complexes to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also identified complexes in Parkinson disease, cardiomyopathies, and muscular dystrophy syndromes that are similarly tissue specific. Our method represents a conceptual scaffold for organism-spanning analyses and reveals an extensive list of tissue-specific draft molecular pathways, both known and unexpected, that might be disrupted in disease.
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Most disease-related genes have tissue-specific expression abnormalities.
“Gene expression and regulation can be highly tissue-specific, and most disease-related genes have tissue-specific expression abnormalities [16, 17].”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [17]
Gene expression and regulation can be highly tissue-specific.
“Gene expression and regulation can be highly tissue-specific, and most disease-related genes have tissue-specific expression abnormalities [16, 17].”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [17]
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- Authors
- Lage, K., Hansen, N. T., Karlberg, E. O., Eklund, A. C., Roque, F. S., Donahoe, P. K., Szallasi, Z., Jensen, T. S., & Brunak, S.
- Affiliations
- Harvard University (US)
- Technical University of Denmark (DK)
- Stockholm University (SE)
- Center for Biological Sequence Analysis, Kemitorvet building 208, Technical University of Denmark, DK-2800 Lyngby, Denmark;
- University of Copenhagen (DK)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-12-30
- Volume
- 105
- Issue
- 52
- Pages
- 20870-20875
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2606902
- OpenAlex
- W2046831513
- Cited by
- 292
- References
- 48
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 12 · 2023: 12 · 2022: 17 · 2021: 11 · 2020: 14 · 2019: 20 · 2018: 15 · 2017: 18 · 2016: 31 · 2015: 26 · 2014: 20 · 2013: 16 · 2012: 23
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD0551-50)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biomedical Text Mining and Ontologies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- tissue-specific gene expression, disease-associated genes, protein complexes, genetic disorders, cancer genes, XY sex reversal, Parkinson's disease, cardiomyopathy, muscular dystrophy, molecular pathways, germline mutations
- MeSH terms
- Female, Gene Expression Regulation, Humans, Male, Oncogenes, Organ Specificity, Ovary, Disorders of Sex Development, Testis, Genome, Human, Databases, Factual, Germ-Line Mutation, Proteome, Genetic Diseases, Inborn, PubMed
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