Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease
Riku Takei, Ann Rosenthal, Tristan Pascart, Richard Reynolds, Tuhina Neogi, Robert Terkeltaub, Sara Tedeschi, Tony Merriman
Affiliation(s):
Division Of Clinical Immunology And Rheumatology, University Of Alabama At Birmingham, Birmingham, Al, United States
Birmingham Department Of Veterans Affairs Health Care System, Birmingham, Alabama, Us
Objective: To carry out the first genome-wide association (GWA) analysis of chondrocalcinosis (CPPD without inflammation) to identify genetic loci of CPPD and to further understand the genetic basis of CPPD and other related diseases.
Methodology: Publicly available GWA summary statistics of chondrocalcinosis for European (EUR; 2,468 cases and 445,620 controls) and African (AFR; 536 cases and 120,708 controls) ancestries were obtained from the Million Veteran Program data set1 (Verma et al., 2024). A genetic variant was considered genome-wide significant if P ≤ 5´10-8. Locus zoom plots3 were generated for significant variants identified from the GWA analysis. Conditional analysis was carried out for the RNF144B locus in the EUR data using GCTA-cojo2 to confirm multiple genetic signals at the locus. Summary statistics of other crystal arthropathy and several other potentially related conditions (osteoarthritis; osteoporosis; pathological fracture; stress fracture; osteopenia or other disorder of bone and cartilage; osteoporosis, osteopenia and pathological fracture) were downloaded to investigate the association of chondrocalcinosis-associated variants with these conditions.
Results: Two loci were identified in both EUR and AFR ancestry at ENPP1 (AFR lead variant = rs11963689, P = 3.8´10-9; EUR lead variant = rs6939185, P = 3.5´10-19) and RNF144B (AFR lead variant = rs9396861, P = 3.4´10-8; EUR lead variant = rs1886248, P = 4.0´10-33), both on chromosome 6 (Figure 1). After conditioning on the EUR lead variant rs1886248, a second lead variant was revealed at the RNF144B locus (rs12524807, conditioned P = 8.3´10-17). There was a significant association at ENPP1 locus (rs11963689, P = 2.1´10-9) in AFR and associations in both ENPP1 (rs766592, P = 1.8´10-17, in high LD (r2 = 0.97) with rs6939185) and RNF144B (rs1886248, P = 2.7´10-31) in EUR for other crystal arthropathy. There was no significant association with other crystal arthropathy at the strong gout loci ABCG2 and SLC2A9. None of the lead variants from chondrocalcinosis were associated with any of the other conditions (P ≥ 2.1´10-3).
Conclusions: GWA analysis of chondrocalcinosis revealed two genetic loci at ENPP1 and RNF144B in both EUR and AFR ancestries. The ENPP1 (ectonucleotide pyrophosphate/phosphodiesterase 1) protein mainly cleaves ATP into AMP and diphosphate, a crucial substrate for formation of CPP crystal. Lack of association of chondrocalcinosis variants with other bone- and cartilage-related conditions is not consistent with a causal role of chondrocalcinosis in these conditions, requiring further study to investigate the causal relationship (for example with Mendelian randomization). These results show a promising start in understanding the genetic basis of CPPD disease and its relationship with other bone-related diseases.
References:
1. Verma, A., Huffman, J. E., Rodriguez, A., Conery, M., Liu, M., Ho, Y-L., Kim, Y., et al. “Diversity and Scale: Genetic Architecture of 2068 Traits in the VA Million Veteran Program.” Science 385, no. 6706 (2024).
2. Yang J., Lee S.H., Goddard M.E. and Visscher P.M.. “GCTA: a tool for Genome-wide Complex Trait Analysis.” Am J Hum Genet. 88(1): 76-82 (2011)
3. Major, T., and Takei, R.. “Locuszoom-like Plots for GWAS Results”. Zenodo, 2021. https://doi.org/10.5281/zenodo.5154379
