Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect

Styrkarsdottir, Unnur; Stefansdottir, Lilja; Thorleifsson, Gudmar; Stefansson, Olafur A.; Saevarsdottir, Saedis; Lund, Sigrun H.; Rafnar, Thorunn; Hoshijima, Kazuyuki; Novak, Kendra; Oreiro, Natividad; Rego-Pérez, Ignacio; Hansen, Channing; Kazmers, Nikolas; Kiemeney, Lambertus A.; Blanco García, Francisco J; Barker, Tyler; Kloppenburg, Margreet; Jurynec, Michel J.; Gudbjartsson, Daniel F.; Jonsson, Helgi; Thorsteinsdottir, Unnur; Stefansson, Kari

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Title

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect

Date

2023-03-17

Citation

Styrkarsdottir U, Stefansdottir L, Thorleifsson G, Stefansson OA, Saevarsdottir S, Lund SH, Rafnar T, Hoshijima K, Novak K, Oreiro N, Rego-Perez I, Hansen C, Kazmers N, Kiemeney LA, Blanco FJ, Barker T, Kloppenburg M, Jurynec MJ, Gudbjartsson DF, Jonsson H, Thorsteinsdottir U, Stefansson K. Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect. Ann Rheum Dis. 2023 Mar 17:ard-2022-223468. Epub ahead of print.

Abstract

[Abstract] Objectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. Methods: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. Results: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4×10-14) and rs11243284 (6p24.3, OR=1.35, p=4.2×10-11) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1×10-18), and rs1800801 (MGP, OR=1.37, p=3.6×10-13) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. Conclusions: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints.