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<p>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 <i>SNRNP70</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月26日

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  • 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,
  • Douglas H. Phanstiel

摘要

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.