Comprehensive profiling of transcriptional regulation in cartilage reveals pathogenesis of osteoarthritis

Cartilage damage is a leading cause of osteoarthritis (OA) etiology, however, the underlying mechanism governing gene expression regulation in this progress is poorly understood. Here, we described a comprehensive profiling of transcriptional regulation of 235 primary human cartilage samples. We identified 3,352 independent significant expression quantitative trait loci (eQTLs) for 3,109 genes. We explored the candidate casual SNP and its underlying regulatory mechanism using our established functional fine-mapping pipeline by integrating the cartilage-specific ATAC-seq data. We identified 117 causal eQTLs that display allele-specific open chromatin (ASoC) and 547 transcription factor binding-disruption (TBD) eQTLs. We conducted cell type-interaction eQTL (ci-eQTL) analyses based on speculated chondrocyte subtype proportions and revealed the regulation relationship of 120 eQTL-gene pairs showed cell type dependency. Further, by integrating with genome-wide association studies (GWASs) data of OA, we nominated 43 candidate effector genes for OA risk loci. We verified that the T allele of the OA risk variant rs11750646 increased the AR binding affinity to an open chromatin region and promoted the expression of an OA-related gene PIK3R1. Altogether, our findings provide new insights into the unique regulatory landscape of cartilage and elucidate potential mechanisms underlying the OA pathogenesis.