{"doi":"10.1101/2022.05.16.492146","title":"3D Chromatin Structure in Chondrocytes Identifies Putative Osteoarthritis Risk Genes","abstract":"ABSTRACT Genome-wide association studies (GWAS) have identified over 100 loci associated with osteoarthrtis (OA) risk, but the majority of OA risk variants are non-coding, making it difficult to identify the impacted genes for further study and therapeutic development. To address this need, we used a multi-omic approach and genome editing to identify and functionally characterize potential OA risk genes. Computational analysis of GWAS and ChIP-seq data revealed that chondrocyte regulatory loci are enriched for OA risk variants. We constructed a chondrocyte specific regulatory network by mapping 3D chromatin structure and active enhancers in human chondrocytes. We then intersected these data with our previously collected RNA-seq dataset of chondrocytes responding to fibronectin fragment (FN-f), a known OA trigger. Integration of the three genomic datasets with recently reported OA GWAS variants revealed a refined set of putative causal OA variants and their potential target genes. One of the novel putative target genes identified was SOCS2 , which was connected to a putative causal variant by a 170 Kb loop and is differentially regulated in response to FN-f. CRISPR-Cas9-mediated deletion of SOCS2 in primary human chondrocytes from three independent donors led to heightened expression of inflammatory markers after FN-f treatment. These data suggest that SOCS2 plays a role in resolving inflammation in response to cartilage matrix damage and provides a possible mechanistic explanation for its influence on OA risk. In total, we identified 56 unique putative OA risk genes for further research and potential therapeutic development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":303285,"datarank":0.15426185452017754,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.05028977743618572,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.05028977743618572,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":489826,"name":"Eric S. Davis","orcid":"0000-0003-4051-3217","position":1,"is_corresponding":false},{"id":365921,"name":"Susan D’Costa","orcid":"0000-0002-8864-2301","position":2,"is_corresponding":false},{"id":466073,"name":"Philip Coryell","orcid":"0000-0001-9991-1987","position":3,"is_corresponding":false},{"id":324327,"name":"Nicole E. Kramer","orcid":"0000-0001-9617-9671","position":4,"is_corresponding":false},{"id":11271,"name":"Karen L. Mohlke","orcid":"0000-0001-6721-153X","position":5,"is_corresponding":false},{"id":404668,"name":"Richard F. Loeser","orcid":"0000-0003-2832-6144","position":6,"is_corresponding":false},{"id":479511,"name":"Brian O. Diekman","orcid":"0000-0001-9055-4282","position":7,"is_corresponding":false},{"id":527040,"name":"Douglas H. Phanstiel","orcid":"0000-0003-2123-0051","position":8,"is_corresponding":false},{"id":512443,"name":"Eliza Thulson","orcid":"0000-0002-8760-3087","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:24.307938Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}