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Katsoula, G. ; Lawrence, J.E.G.* ; Arruda, A.L. ; Tutino, M. ; Balogh, P.* ; Southam, L. ; Swift, D.* ; Behjati, S.* ; Teichmann, S.A.* ; Wilkinson, J.M.* ; Zeggini, E.

Primary cartilage transcriptional signatures reflect cell-type-specific molecular pathways underpinning osteoarthritis.

Am. J. Hum. Genet. 111, 2735-2755 (2024)
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Translational efforts in osteoarthritis are hampered by a gap in our understanding of disease processes at the molecular level. Here, we present evidence of pronounced transcriptional changes in high- and low-disease-grade cartilage tissue, pointing to embryonic processes involved in disease progression. We identify shared transcriptional programs between osteoarthritis cartilage and cell populations in the human embryonic and fetal limb, pointing to increases in pre-hypertrophic chondrocytes' transcriptional programs in low-grade cartilage and increases in osteoblastic signatures in high-grade disease tissue. We find that osteoarthritis genetic risk signals are enriched in six gene co-expression modules and show that these transcriptional signatures reflect cell-type-specific expression along the endochondral ossification developmental trajectory. Using this network approach in combination with causal inference analysis, we present evidence of a causal effect on osteoarthritis risk for variants associated with the expression of ten genes that have not been previously reported as effector genes in genome-wide association studies in osteoarthritis. Our findings point to key molecular pathways as drivers of cartilage degeneration and identify high-value drug targets and repurposing opportunities.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Rna Sequencing ; Cell-type-specific Expression ; Chondrocyte Populations ; Disease Pathways ; Endochondral Ossification ; Gene Co-expression Networks ; Gene Set Analysis ; Osteoarthritis; Endochondral Ossification; Gene-expression; Hypertrophic Chondrocytes; Progression; Calcification; Instability; Program; Growth
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 111, Issue: 12, Pages: 2735-2755 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-506700-001
G-506701-001
Grants Wellcome Trust
DOI 10.1016/j.ajhg.2024.10.019
WOS ID 001407004200001
Scopus ID 85210529890
PubMed ID 39579762
Erfassungsdatum 2024-11-27
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