Transcriptome regulation analysis in osteoarthritis primary tissues identifies high-confidence effector genes

Osteoarthritis, a whole-joint degenerative disorder, is a major public health burden that affects nearly 600 million individuals worldwide, but no disease-modifying treatment exists. Molecular profiling of relevant tissues is crucial for understanding the biological mechanisms underlying disease development. Here, we generate a comprehensive map of transcriptional regulation in disease-relevant primary tissues from knee osteoarthritis patients: macroscopically intact (low-grade, N=263) and degenerated (high-grade, N=216) cartilage, synovium (N=278), and fat pad (N=94). Of 9,738 unique expression quantitative trait loci (eQTL)-associated genes, 60.6% have not been reported previously. Using the largest osteoarthritis genome-wide association study (GWAS) to date, we find colocalization evidence with 117 genes, 67 of which had not been identified as effector genes before. We prioritise 38 high-confidence effector genes for osteoarthritis, based on multiple lines of molecular and functional genomics evidence, including MUSTN1, which is implicated in cartilage integrity. Our study provides insights into the molecular mechanisms underpinning osteoarthritis and offers much-needed drug repurposing opportunities.