A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults
A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults
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.
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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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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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 GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults.
Arthritis & Rheumatology.
(doi:10.1002/art.42451).
Abstract
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.
Text
Arthritis Rheumatology - 2023 - Faber - A GWAS meta‐analysis of alpha angle suggests cam‐type morphology may be a
- Accepted Manuscript
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Accepted/In Press date: 13 January 2023
e-pub ahead of print date: 20 January 2023
Additional Information:
For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Funding and grant award information: BGF is supported by a Medical Research Council (MRC) clinical research training fellowship (MR/S021280/1). RE, MF, FS are supported, and this work is funded by a Wellcome Trust collaborative award (reference number 209233). CL is funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (223267/Z/21/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant numbers 080280/Z/06/Z, 20378/Z/16/Z, 223267/Z/21/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. NCH acknowledges support from the MRC and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton. BGF, MF, AEH, GDS, JHT work in the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the MRC (MC_UU_00011/1). JPK is funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938).
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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: 02 Mar 2023 02:39
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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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