Objective The genetic basis of calcium pyrophosphate deposition (CPPD) disease is largely unknown. This limits the development of therapeutic strategies. We aimed to analyze 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 chondrocalcinosis and for crystal arthropathy from the Veterans Affairs Million Veteran Program in people of African (AFR) and European (EUR) ancestry. Included were 3,004 (536 AFR and 2,468 EUR) cases for chondrocalcinosis and 3,766 (700 AFR and 3,066 EUR) cases for crystal arthropathy. Our primary analysis was in chondrocalcinosis with secondary analysis in crystal arthropathy. We tested for colocalization of chondrocalcinosis genetic association signals with genetic control of gene expression.

Results There were two genome-wide significant loci for chondrocalcinosis in both AFR and EUR, both on chromosome 6 (signals within the ENPP1 and RNF144B genes). Findings were supported by analysis of the crystal arthropathy cohort. Colocalization 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 associated with increased ENPP1 expression.

Conclusion ENPP1 encodes ectonucleotide pyrophosphatase / phosphodiesterase family member 1 that produces AMP and pyrophosphate, potentially contributing to the formation of calcium pyrophosphate crystals. Selective ENPP1 inhibitors developed for infectious disease and cancer could be repurposed for the treatment of chondrocalcinosis and CPPD disease.

TRM declares consulting fees from Variantbio unrelated to the content of this study. SKT declares consulting fees for Novartis, Avalo Therapeutics, Merck, Kyowa Kirin, Alexion and Fresenius Kabi unrelated to the content of this study.

This work was supported in part by Merit Review I01 BX004454 from the United States Department of Veteran's Affairs (to AR) and in part by Rheumatology Research Foundation R Bridge (to SKT).

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