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

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.

Keywords: Bone Density; Osteoarthritis; Polymorphism, Genetic.

Figure 1

Manhattan plot of the genome-wide analysis of erosive hand osteoarthritis The p values (−log10) are plotted against their respective positions on each chromosome. Results are shown for all variants with significance level p<0.001 and imputation information greater than 0.8.

Figure 2

Loss of bmp6 causes erosive-like phenotypes in the zebrafish vertebral precursors. (A–C’). Analysis of cartilage (blue) and bone (red) in the vertebral column of 14 days post fertilisation wild-type (WT) and bmp6^+/- zebrafish larvae. (A, A’) WT larvae have a normally segmented and ossified centra (vertebral precursors) and neural (na) and hemal arches (ha), whereas (B, C’) bmp6^{+/ −} have multiple defects, including bone erosions (arrow in B and B’), structural defects in the centra (arrowhead in B, C and C’), ectopic cartilage formation (arrow in C’), and disruptions in the neural and hemal arches (asterisks in C’). No defects are observed in the cartilaginous structures of the fins. All images are lateral views with anterior to the left.

Figure 3

Genetic correlation between EHOA and other OA subtypes and diseases/traits The genetic correlation coefficient (r_g) and SE, of genetic correlation between EHOA and other OA subtypes, any OA (which includes all types of OA), and several diseases/traits are shown. HGS is hand grip strength, FN_BMD is femoral neck bone mineral density, LS_BMD is lumbar spine bone mineral density, and RA is rheumatoid arthritis. BMD, bone mineral density; EHOA, erosive hand osteoarthritis; LS-BMD, lumbar spine BMD; OA, osteoarthritis.