| Title: | The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses |
| Journal: | EBioMedicine |
| Published: | 22 Aug 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37619450/ |
| DOI: | https://doi.org/10.1016/j.ebiom.2023.104759 |
| URL: | https://pure.eur.nl/files/98846749/1-s2.0-S2352396423003249-main.pdf |
Publication 9722
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Abstract
BACKGROUND: Hip minimum joint space width (mJSW) 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 (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest.</p>
METHODS: GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA 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.</p>
FINDINGS: 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82-1.18]). 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.</p>
INTERPRETATIONS: One group of mJSW loci reduce 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 HOA risk via a growth-related mechanism.</p>
FUNDING: Primarily funded by the Medical Research Council and Wellcome Trust.</p>
22 Authors
- Benjamin G. Faber
- Monika Frysz
- Cindy G. Boer
- Daniel S. Evans
- Raja Ebsim
- Kaitlyn A. Flynn
- Mischa Lundberg
- Lorraine Southam
- April Hartley
- Fiona R. Saunders
- Claudia Lindner
- Jennifer S. Gregory
- Richard M. Aspden
- Nancy E. Lane
- Nicholas C. Harvey
- David M. Evans
- Eleftheria Zeggini
- George Davey Smith
- Timothy Cootes
- Joyce Van Meurs
- John P. Kemp
- Jonathan H. Tobias
1 Application
| Application ID | Title |
|---|---|
| 17295 | AUtomated Generation of Musculoskeletal phENotypes from the UK biobank exTended imaging study (AUGMENT Study) |
Enabling scientific discoveries that improve human health