Rice SJ, et al. - Genome-wide genotyping and cartilage DNA methylation array data was assessed in a discovery screen of novel osteoarthritis (OA, a common, age-related disease of synovial joints characterized by the thinning of articular cartilage) risk loci by the experts in order to ascertain methylation quantitative trait loci (mQTLs) correlating with OA risk alleles and offered mechanistic characterization as a means of target gene prioritization. Four novel OA mQTLs were identified. Nine CpG sites where methylation was associated with OA risk genotype, with 5 of the CpG sites, were the most PLEC gene and produced 2 distinct clusters. Independent targets of the OA risk were PLEC and the adjacent gene GRINA. PLEC and GRINA expression QTLs working in cartilage, as well as methylation-expression QTLs running on the 2 genes were recognized. Also, between OA hip and non-OA hip cartilage, differential expression was exhibited by GRINA and PLEC. Hence, PLEC was concluded encoding plectin (a cytoskeletal protein that maintains tissue integrity by regulating intracellular signaling in response to mechanical stimuli) whereas GRINA encoded the ionotropic glutamate receptor TMBIM3 (transmembrane BAX inhibitor 1 motif-containing protein family member 3; controls cell survival). Furthermore, it was assumed that in a joint predisposed to OA, expression of such genes changed to battle aberrant biomechanics and that this was epigenetically controlled. However, the carriage of the OA risk-conferring allele at this locus prevented this response and contributed to disease progression.