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

FABER, Benjamin G., FRYSZ, Monika, HARTLEY, April E., EBSIM, Raja, BOER, Cindy G., SAUNDERS, Fiona R., GREGORY, Jennifer S., ASPDEN, Richard M., HARVEY, Nicholas C., SOUTHAM, Lorraine, GILES, William, LE MAITRE, Christine, WILKINSON, J. Mark, VAN MEURS, Joyce B.J., ZEGGINI, Eleftheria, COOTES, Timothy, LINDNER, Claudia, KEMP, John P., DAVEY SMITH, George and TOBIAS, Jonathan H. (2023). 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. Arthritis & Rheumatology.

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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). 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. 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). 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.

Item Type:	Article
Additional Information:	** Article version: VoR ** From Wiley via Jisc Publications Router ** Licence for VoR version of this article: http://creativecommons.org/licenses/by/4.0/ **Journal IDs: issn 2326-5191; issn 2326-5205 **Article IDs: publisher-id: art42451 **History: published_online 09-04-2023; accepted 17-01-2023; rev-recd 08-11-2022; submitted 02-08-2022
Uncontrolled Keywords:	Full Length
Identification Number:	https://doi.org/10.1002/art.42451
SWORD Depositor:	Colin Knott
Depositing User:	Colin Knott
Date Deposited:	14 Apr 2023 16:42
Last Modified:	11 Oct 2023 16:00
URI:	https://shura.shu.ac.uk/id/eprint/31753

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