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Integrative Omics Analysis of Human Cartilage in Aging and Osteoarthritis

This study investigates the tissue- and cell-type-specific genetic regulatory architecture of human knee joint tissues to elucidate the molecular underpinnings of osteoarthritis (OA). Matched cartilage, meniscus, and synovium samples were obtained from unrelated donors, comprising healthy organ donors with macroscopically normal cartilage and patients undergoing total knee arthroplasty (TKA) for severe OA. We performed whole-genome sequencing (WGS), bulk RNA sequencing of cartilage (n=113), meniscus (n=112), and synovium (n=81), and single-nucleus multiome (joint snATAC-seq + snRNA-seq) profiling on a subset of donors. By integrating these datasets, we performed cis-eQTL mapping in bulk and deconvolved cell-type-specific contexts across all three tissues, colocalization analysis with OA GWAS summary statistics (Regulatory Trait Concordance and coloc), rare variant promoter analysis, and chromatin-informed fine-mapping.

In this updated version, the study has been expanded to a total of 220 unrelated donors. We added whole-genome sequencing (WGS) for 102 additional donors; small RNA sequencing (Illumina) of cartilage (n=92) and meniscus (n=88) to profile microRNA regulation; and long-read RNA sequencing (Oxford Nanopore PromethION P2) of cultured cartilage, meniscus, and synovium cells with and without interleukin-1β (IL-1β) stimulation (n=31) to capture full-length transcript isoforms of the inflammatory response.

The data available through dbGaP include raw WGS sequence (FASTQ/CRAM), bulk RNA-seq sequence (FASTQ) from cartilage, meniscus, and synovium, small RNA-seq sequence (FASTQ), long-read RNA-seq (unaligned BAM), associated metadata, and donor phenotypic information.