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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.

Original languageEnglish
Pages (from-to)900-909
Number of pages10
JournalArthritis and Rheumatology
Issue number6
Early online date20 Jan 2023
Publication statusE-pub ahead of print - 20 Jan 2023

Bibliographical note

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.

Structured keywords

  • Bristol Population Health Science Institute


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