| Title: | A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults |
| Journal: | Arthritis & Rheumatology |
| Published: | 9 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36662418/ |
| DOI: | https://doi.org/10.1002/art.42451 |
| URL: | https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/art.42451 |
Publication 11317
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Abstract
OBJECTIVE: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA).</p>
METHODS: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10-8 ) were used as AA genetic instrument for 2-sample MR analysis.</p>
RESULTS: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (rg = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10-5 ).</p>
CONCLUSION: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.</p>
20 Authors
- Benjamin G. Faber
- Monika Frysz
- April E. Hartley
- Raja Ebsim
- Cindy G. Boer
- Fiona R. Saunders
- Jennifer S. Gregory
- Richard M. Aspden
- Nicholas C. Harvey
- Lorraine Southam
- William Giles
- Christine L. Le Maitre
- J. Mark Wilkinson
- Joyce B. J. van Meurs
- Eleftheria Zeggini
- Timothy Cootes
- Claudia Lindner
- John P. Kemp
- George Davey Smith
- 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