A splicing-based multitissue association study of joint transcriptomes identified susceptibility genes for...

Area of Science:

• Genetics
• Molecular Biology
• Rheumatology

Background:

• Osteoarthritis (OA) is a prevalent degenerative joint disease impacting quality of life and imposing economic burdens.
• Genome-wide association studies (GWAS) have identified OA-associated genetic loci, but their functional mechanisms remain largely unknown.
• Transcriptome-wide association studies (TWAS) offer novel approaches to investigate the genetic underpinnings of OA by integrating gene expression and GWAS data.

Purpose of the Study:

• To identify and validate key genes associated with osteoarthritis (OA) using integrated cross-tissue and single-tissue TWAS.
• To investigate the functional role of identified genes, particularly latent transforming growth factor beta binding protein 1 (LTBP1), in OA pathogenesis.
• To explore the expression characteristics, differentiation trajectories, and cell-cell communication patterns of LTBP1 in distinct cell subtypes.

Main Methods:

• Integrated cross-tissue and single-tissue TWAS using UTMOST, FUSION, and MAGMA methods.
• Single-cell sequencing to analyze LTBP1 expression, pseudotemporal trajectories, and cell-to-cell communication.
• Validation of LTBP1 as a regulator of transforming growth factor-beta (TGF-β) signaling.

Main Results:

• Multiple candidate genes for OA were identified, with LTBP1 showing significant association in both cross-tissue and single-tissue analyses (FDR < 0.05).
• LTBP1 was confirmed as a key regulator of the TGF-β signaling pathway.
• Single-cell analysis revealed differential LTBP1 expression in chondrocyte subtypes, enrichment of Notch signaling, and a dynamic role in chondrocyte differentiation.

Conclusions:

• LTBP1 plays a significant role in osteoarthritis pathogenesis.
• High LTBP1 expression activates TGF-β and VEGF signaling pathways, potentially influencing extracellular matrix formation and immune responses in OA.
• LTBP1's dynamic regulatory role in chondrocyte differentiation highlights its importance in understanding OA.