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
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
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 (r
g = 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.
900-909
Faber, Benjamin G.
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Frysz, Monika
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Hartley, April E.
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Ebsim, Raja
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Boer, Cindy G.
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Saunders, Fiona R.
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Gregory, Jennifer S.
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Aspden, Richard M.
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Harvey, Nicholas C.
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Southam, Lorraine
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Giles, William
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Le Maitre, Christine L.
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Wilkinson, J. Mark
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van Meurs, Joyce B.J.
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Zeggini, Eleftheria
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Cootes, Timothy
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Lindner, Claudia
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Kemp, John P.
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Davey Smith, George
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Tobias, Jonathan H.
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June 2023
Faber, Benjamin G.
8639d027-09db-48fe-8213-0ab271f9701c
Frysz, Monika
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Hartley, April E.
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Ebsim, Raja
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Boer, Cindy G.
688bdc35-7d58-476a-9616-369509ec5383
Saunders, Fiona R.
a51cc79d-0928-4ab6-a479-3972c974670b
Gregory, Jennifer S.
6995d8fa-b32b-4f7c-aa15-8146acb4fd67
Aspden, Richard M.
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Harvey, Nicholas C.
ce487fb4-d360-4aac-9d17-9466d6cba145
Southam, Lorraine
93ceaec8-5623-4384-8e04-3c6d908cdbb6
Giles, William
5493437f-82e7-4898-ada2-2b81d09eb86c
Le Maitre, Christine L.
bfb3d65e-2044-4d26-9ac9-926c8ab4212b
Wilkinson, J. Mark
744255c1-7fc8-4dd6-96f6-156035681e96
van Meurs, Joyce B.J.
90f66a65-5df4-4442-85fc-94610727aaf3
Zeggini, Eleftheria
b487a5f2-c446-4d9b-b964-9ff8823074ff
Cootes, Timothy
f82f878a-ab1d-426c-9510-afa3f6de7aef
Lindner, Claudia
03ee5726-0741-4170-8375-659292641028
Kemp, John P.
e55b0aa0-e9b7-4c08-b43e-7e8fc4132baf
Davey Smith, George
a7a39f65-e054-40e4-b613-baa28873b4c2
Tobias, Jonathan H.
514342d7-3491-4a7b-bbeb-b00dcf244daa
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 L., 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, 75 (6), .
(doi:10.1002/art.42451).
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 (r
g = 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.
Text
Arthritis Rheumatology - 2023 - Faber - A GWAS meta‐analysis of alpha angle suggests cam‐type morphology may be a
- Accepted Manuscript
More information
Accepted/In Press date: 13 January 2023
e-pub ahead of print date: 20 January 2023
Published date: June 2023
Additional Information:
Funding Information:
The authors would like to thank the Musculoskeletal Research Unit patient and public involvement group at the University of Bristol for their input into planning our research and Dr. Martin Williams, a consultant musculoskeletal radiologist at North Bristol NHS Trust, who provided substantial training and expertise for this study. The authors would also like to thank the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The authors acknowledge the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands, for execution of the generation and management of GWAS genotype data for the Rotterdam Study (I, II, and III). Finally, the authors would like to thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Linda Broer, PhD, for the creation of the imputed data, and Mathijs Versteeg for creating the alpha angle data.
Publisher Copyright:
© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
Identifiers
Local EPrints ID: 474696
URI: http://eprints.soton.ac.uk/id/eprint/474696
ISSN: 2326-5191
PURE UUID: 27eb26f1-66ce-4d87-b7f8-ed7424b1c8f8
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Date deposited: 01 Mar 2023 17:58
Last modified: 17 Mar 2024 02:59
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Contributors
Author:
Benjamin G. Faber
Author:
Monika Frysz
Author:
April E. Hartley
Author:
Raja Ebsim
Author:
Cindy G. Boer
Author:
Fiona R. Saunders
Author:
Jennifer S. Gregory
Author:
Richard M. Aspden
Author:
Lorraine Southam
Author:
William Giles
Author:
Christine L. Le Maitre
Author:
J. Mark Wilkinson
Author:
Joyce B.J. van Meurs
Author:
Eleftheria Zeggini
Author:
Timothy Cootes
Author:
Claudia Lindner
Author:
John P. Kemp
Author:
George Davey Smith
Author:
Jonathan H. Tobias
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