Response eQTLs, chromatin accessibility, and 3D chromatin structure in chondrocytes provide mechanistic insight into osteoarthritis risk

Nicole E. Kramer, Seyoun Byun, Philip Coryell, Susan D'Costa, Eliza Thulson, Hyun Ah Kim, Sylvie M. Parkus, Marielle L. Bond, Emma R. Klein, Jacqueline Shine, Susanna Chubinskaya, Michael I. Love, Karen L. Mohlke, Brian O. Diekman, Richard F. Loeser, Douglas H. Phanstiel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number100738
JournalCell Genomics
Volume5
Issue number1
DOIs
StatePublished - Jan 8 2025

Keywords

  • 3D chromatin structure
  • chondrocyte
  • chromatin accessibility
  • colocalization
  • eQTL

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Genetics

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