Pos0224 Primary Osteoarthritis Chondrocyte Map of Chromatin Conformation Reveals Novel Effector Genes

Background: Osteoarthritis (OA) is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated DNA sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organization in 3D space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Objectives: Our aim was to generate the first whole genome wide chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel effector genes for osteoarthritis. Methods: Primary chondrocytes collected from 8 knee osteoarthritis patients underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results to identify variants involved in gene regulation via enhancer-promoter interactions. Results: We identified 345 genetic variants residing within chromatin loop anchors that are associated with 77 osteoarthritis GWAS signals. Ten of these variants reside directly in enhancer regions of 10 newly described active enhancer-promoter loops, identified with multiomics analysis of publicly available ChIP-Seq and ATAC-Seq data from primary knee chondrocyte cells, pointing to 3 new candidate effector genes. Those genes SPRY4, SLC44A2 and PAPPA are known to be involved in osteoarthritis. For example, PAPPA is directly associated with the turnover of IGF-1 proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes. Conclusion: We have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D-genomics with large-scale genetic association and epigenetic data, we identify novel candidate effector genes for osteoarthritis, which enhance our understanding of disease and can serve as putative high-value novel drug targets. REFERENCES: NIL. Acknowledgements: This work was funded by the Wellcome Trust (award references 207491/Z/17/Z and 215207/Z/19/Z), Versus Arthritis (award reference 21754), NIHR Manchester Biomedical Research Centre. Disclosure of Interests: None declared.