Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease.

Objectives: The genetic basis of calcium pyrophosphate deposition (CPPD) disease is unknown. This limits the development of therapeutic strategies. We aimed to analyse a genome-wide association study (GWAS) on a large administrative database to identify new candidate causal genes for CPPD disease.

Methods: We used publicly available GWAS summary statistics for Phecode-defined chondrocalcinosis and crystal arthropathy from the Veterans Affairs Million Veteran Program in people of African (AFR) and European (EUR) ancestry. Included were 3004 (536 AFR and 2468 EUR) cases for chondrocalcinosis and 3766 (700 AFR and 3066 EUR) cases for crystal arthropathy (operationally interpreted as calcium crystal arthropathy). Our primary analysis was in chondrocalcinosis, with secondary analysis in crystal arthropathy. We tested for colocalisation of chondrocalcinosis genetic association signals with genetic control of gene expression.

Results: There were 2 genome-wide significant loci for chondrocalcinosis in both AFR and EUR cases, both on chromosome 6 (signals within the ENPP1 and RNF144B genes). Findings were supported by analysis of the crystal arthropathy cohort. Colocalisation analysis of chondrocalcinosis genetic association signals with genetic control of gene expression and alternative splicing further supported ENPP1 and RNF144B as candidate casual genes. At ENPP1, the allele that increases the risk for chondrocalcinosis was associated with increased ENPP1 expression.

Conclusions: ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (NPP1) that produces adenosine monophosphate (AMP) and inorganic pyrophosphate which, together with calcium ions, leads to the formation of calcium pyrophosphate crystals. Selective NPP1 inhibitors developed for infectious disease and cancer could be tested as treatment for CPPD disease.