Hip joint space width is causally related to hip osteoarthritis risk via distinct protective and susceptibility mechanisms: findings from a genome-wide association study meta-analysis

Objective Minimum joint space width (mJSW) from 2-dimensional images provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and use them to (ii) examine causal effects of mJSW on hip osteoarthritis (HOA) risk. Methods GWAS meta-analysis of hip mJSW derived from plain X-rays (four cohorts) or DXA (one cohort) was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA. Results 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci (35 novel), were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA ( β IVW -0.01 [95% CI -0.19, 0.17]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life. Conclusions GWAS and MR analyses suggested one group of mJSW loci reduces HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to mJSW and HOA risk via a growth-related mechanism.