The methylomic landscape of human articular cartilage development contains epigenetic signatures of osteoarthritis risk.

Increasing evidence is emerging to link age-associated complex musculoskeletal diseases, including osteoarthritis (OA), to developmental factors. Multiple studies have shown a functional role for DNA methylation in the genetic mechanisms of OA risk using articular cartilage samples taken from aged individuals, yet knowledge of temporal changes to the methylome during human cartilage development is limited. We quantified DNA methylation at ∼700,000 individual CpGs across the epigenome of developing human chondrocytes in 72 samples ranging from 7 to 21 post-conception weeks. We identified significant changes in 3% of all CpGs and >8,200 developmental differentially methylated regions. We further identified 24 loci at which OA genetic variants colocalize with methylation quantitative trait loci. Through integrating developmental and mature human chondrocyte datasets, we find evidence for functional effects exerted solely in development or throughout the life course. This will have profound impacts on future approaches to translating genetic pathways for therapeutic intervention.