Faber, B.G. orcid.org/0000-0003-4102-0190, Frysz, M. orcid.org/0000-0001-5729-778X, Hartley, A.E. orcid.org/0000-0003-4932-1588 et al. (17 more authors) (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). pp. 900-909. ISSN 2326-5191
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Aging; Human Genome; Clinical Research; Genetics; Prevention |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 01 Mar 2023 11:01 |
Last Modified: | 27 Sep 2024 15:59 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/art.42451 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:196886 |