Genetic and population analyses implicate thyroid-related regulation of RNF144B in chondrocalcinosis

Chondrocalcinosis, characterized by calcium crystal deposition within articular cartilage, affects 5-15% of the general population and has recently been identified as an osteoarthritis risk factor. However, Its biological pathways remain unclear. We conducted a genome-wide association study of radiographically defined chondrocalcinosis knee and hand to identify its genetic determinants.

GWAS analyses of knee, hand, and combined chondrocalcinosis included up to 9,317 Rotterdam Study participants, with replication inthe Versus Arthritis Osteoarthritis Genetics study and the Multicenter Osteoarthritis Study. Translational annotation prioritized effector genes. Associations between circulating thyroid-stimulating hormone (TSH) and knee chondrocalcinosis were evaluated in the Rotterdam Study (n = 2,892).

We identified two genome-wide significant loci for knee chondrocalcinosis: a novel signal (rs62424495) at the ENPP1-locus (β = -0.21, P = 2.6 × 10^-9) and a previously reported signal (rs6927663) at the RNF144B-locus (β = 0.12, P = 8.8 × 10^-10). Translational genomic analyses prioritized ENPP1 and RNF144B as candidate effector genes, with evidence indicating that the chondrocalcinosis variant likely affects RNF144B regulation in thyroid tissue.The lead variant colocalized with circulating TSH levels (β = 0.027, P = 2 × 10^-14). population analysis found that higher TSH levels were cross-sectionally associated with presence and severity of knee chondrocalcinosis.

These findings identify genetic loci for radiographic chondrocalcinosis and offer hypothesis-generating evidence of thyroid-related pathways in its susceptibility, providing insight into molecular mechanisms underlying joint mineralization.