Response splicing quantitative trait loci in primary human chondrocytes identify putative osteoarthritis risk genes

Seyoun Byun, Jacqueline Shine, Philip Coryell, Nicole E. Kramer, Susan D’Costa, Eliza Thulson, Sylvie M. Parkus, Susan Chubinskaya, Richard F. Loeser (), Brian O. Diekman () and Douglas H. Phanstiel ()
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Seyoun Byun: University of North Carolina
Jacqueline Shine: University of North Carolina
Philip Coryell: University of North Carolina
Nicole E. Kramer: University of North Carolina
Susan D’Costa: University of North Carolina
Eliza Thulson: University of North Carolina
Sylvie M. Parkus: University of North Carolina
Susan Chubinskaya: University of Texas Medical Branch
Richard F. Loeser: University of North Carolina
Brian O. Diekman: University of North Carolina
Douglas H. Phanstiel: University of North Carolina

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Osteoarthritis affects millions worldwide, yet effective treatments remain elusive due to poorly understood molecular mechanisms. While genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated loci, identifying the genes impacted at each locus remains challenging. We investigate alternative splicing using RNA-sequencing data from 101 human chondrocyte samples treated with phosphate-buffered saline or fibronectin fragment, an osteoarthritis trigger. We identified 590 differentially spliced genes between conditions, with FN-f inducing splicing events similar to those in primary osteoarthritis tissue. CRISPR/Cas9 mimicking of an SNRNP70 splicing event observed in osteoarthritis induced an osteoarthritis-like expression pattern. Integration with genotyping data revealed 7188 splicing quantitative trait loci (sQTL) affecting 3056 genes, including 738 and 343 condition-specific sQTLs for resting and fibronectin fragment, respectively. Colocalization with osteoarthritis GWAS identified 6 putative risk genes. Our study highlights the significant impact of alternative splicing in osteoarthritis and provides potential therapeutic targets.

Date: 2025
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DOI: 10.1038/s41467-025-63299-0

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