Kreitmaier, P., Suderman, M., Southam, L. et al. (7 more authors) (2022) An epigenome-wide view of osteoarthritis in primary tissues. The American Journal of Human Genetics, 109 (7). pp. 1255-1271. ISSN 0002-9297
Abstract
Osteoarthritis is a complex degenerative joint disease. Here, we investigate matched genotype and methylation profiles of primary chondrocytes from macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage and from synoviocytes collected from 98 osteoarthritis-affected individuals undergoing knee replacement surgery. We perform an epigenome-wide association study of knee cartilage degeneration and report robustly replicating methylation markers, which reveal an etiologic mechanism linked to the migration of epithelial cells. Using machine learning, we derive methylation models of cartilage degeneration, which we validate with 82% accuracy in independent data. We report a genome-wide methylation quantitative trait locus (mQTL) map of articular cartilage and synovium and identify 18 disease-grade-specific mQTLs in osteoarthritis cartilage. We resolve osteoarthritis GWAS loci through causal inference and colocalization analyses and decipher the epigenetic mechanisms that mediate the effect of genotype on disease risk. Together, our findings provide enhanced insights into epigenetic mechanisms underlying osteoarthritis in primary tissues.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | DNA methylation; osteoarthritis; cartilage; synovium; methylation QTL; chondrocyte; synoviocyte; machine learning; EWAS |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 01 Jul 2022 11:30 |
Last Modified: | 10 Feb 2023 12:32 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.ajhg.2022.05.010 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:188633 |