A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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OBJECTIVES: To examine the genetic architecture of cam morphology, using alpha angle (AA) as a proxy measure, we conducted an AA genome wide association study (GWAS), followed by Mendelian randomisation (MR) to evaluate its causal relationship with hip osteoarthritis (HOA).

METHODS: Observational analyses examined associations between AA derived from hip DXA scans in UK Biobank (UKB), and radiographic HOA (rHOA) and subsequent total hip replacement (THR). Afterwards, an AA GWAS meta-analysis was performed (n=44,214), using AA previously derived in the Rotterdam Study (RS). Linkage disequilibrium score regression assessed the genetic correlation between AA and HOA. Genetic associations with P<5x10-8 instrumented AA for two-sample MR.

RESULTS: DXA-derived AA showed expected associations between AA and rHOA (OR 1.63 [95% CI 1.58-1.67]) and THR (HR 1.45 [1.33-1.59]) in UKB. The heritability of AA was 10% and AA had a moderate genetic correlation with HOA (rg =0.26 [0.10-0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on HOA risk (inverse variance weighted (IVW): OR=1.84 [1.14-2.96], P 0.01). In contrast, genetic predisposition for HOA had stronger evidence of a causal effect on increased AA (IVW: β=0.09 [0.04-0.13], P 4.58 x 10-05 ).

CONCLUSIONS: Expected observational associations between AA and related clinical outcomes provided face-validity for the DXA-derived AA measures. Evidence of bidirectional associations between AA and HOA, particularly in the reverse direction, suggests that hip shape modelling secondary to a genetic predisposition to HOA contributes to the well-established relationship between HOA and cam morphology in older adults.

Original languageEnglish
JournalArthritis and Rheumatology
Early online date20 Jan 2023
Publication statusE-pub ahead of print - 20 Jan 2023

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  • Bristol Population Health Science Institute


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