Response eQTLs, chromatin accessibility, and 3D chromatin structure in chondrocytes provide mechanistic insight into osteoarthritis risk
Osteoarthritis (OA) poses a significant healthcare burden with limited treatment options. While genome-wide association studies (GWASs) have identified over 100 OA-associated loci, translating these findings into therapeutic targets remains challenging. To address this gap, we mapped gene expression, chromatin accessibility, and 3D chromatin structure in primary human articular chondrocytes in both resting and OA-mimicking conditions. We identified thousands of differentially expressed genes, including those associated with differences in sex and age. RNA sequencing in chondrocytes from 101 donors across two conditions uncovered 3,782 unique eGenes, including 420 that exhibited strong and significant condition-specific effects. Colocalization with OA GWAS signals revealed 13 putative OA risk genes, 6 of which have not been previously identified. Chromatin accessibility and 3D chromatin structure provided insights into the mechanisms and conditional specificity of these variants. Our findings shed light on OA pathogenesis and highlight potential targets for therapeutic development.
Authors
- Marielle L. Bond (ORCID: https://orcid.org/0000-0002-8334-6095)
- Douglas H. Phanstiel (ORCID: https://orcid.org/0000-0003-2123-0051)
- Emma R. Klein (ORCID: https://orcid.org/0009-0005-8661-6694)
- Jacqueline Shine (ORCID: https://orcid.org/0000-0002-9640-4741)
- Michael I. Love (ORCID: https://orcid.org/0000-0001-8401-0545)
- Karen L. Mohlke (ORCID: https://orcid.org/0000-0001-6721-153X)
- Seyoun Byun (ORCID: https://orcid.org/0000-0002-2915-6012)
- Nicole E. Kramer (ORCID: https://orcid.org/0000-0001-9617-9671)
- Richard F. Loeser (ORCID: https://orcid.org/0000-0003-2832-6144)
- Eliza Thulson (ORCID: https://orcid.org/0000-0002-8760-3087)
- Brian O. Diekman (ORCID: https://orcid.org/0000-0001-9055-4282)
- Susan D’Costa (ORCID: https://orcid.org/0000-0002-8864-2301)
- Philip Coryell (ORCID: https://orcid.org/0000-0001-9991-1987)
- Sylvie M. Parkus
- HyunAh Kim
- Susanna Chubinskaya
Institutions
- University of North Carolina at Chapel Hill (US)
- Rush University Medical Center (US)
- North Carolina State University (US)
- UNC/NCSU Joint Department of Biomedical Engineering (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.xgen.2024.100738
- Citations
- 11
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 10.45
Funders
- National Science Foundation
- Rush University
- National Institutes of Health
- National Human Genome Research Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Center for Advancing Translational Sciences