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

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

doi:10.1002/art.42451

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 Rheumatol. 2023 Jun;75(6):900-909. doi: 10.1002/art.42451. Epub 2023 Apr 9.

Authors

Benjamin G Faber¹, Monika Frysz¹, April E Hartley², Raja Ebsim³, Cindy G Boer⁴, Fiona R Saunders⁵, Jennifer S Gregory⁵, Richard M Aspden⁵, Nicholas C Harvey⁶, Lorraine Southam⁷, William Giles⁸, Christine L Le Maitre⁹, J Mark Wilkinson⁸, Joyce B J van Meurs¹⁰, Eleftheria Zeggini¹¹, Timothy Cootes³, Claudia Lindner³, John P Kemp¹², George Davey Smith², Jonathan H Tobias¹

Affiliations

¹ Musculoskeletal Research Unit, Translational Health Sciences, and Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, UK.
² Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, UK.
³ Division of Informatics, Imaging and Data Science, The University of Manchester, UK.
⁴ Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
⁵ Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, UK.
⁶ Medical Research Council Lifecourse Epidemiology Centre, University of Southampton, UK, and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, UK.
⁷ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁸ Department of Oncology and Metabolism, The University of Sheffield, UK.
⁹ Biomolecular Sciences Research Centre, Sheffield Hallam University, UK.
¹⁰ Department of Internal Medicine and Department of Orthopaedics & Sports Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹¹ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany, and TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Germany.
¹² Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, UK, and The University of Queensland Diamantina Institute and Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.

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.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Arthroplasty, Replacement, Hip*
Causality
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Observational Studies as Topic
Osteoarthritis, Hip* / diagnostic imaging
Osteoarthritis, Hip* / genetics
Osteoarthritis, Hip* / surgery
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding