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).
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 PResults
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).
Expected observational associations between AA and related clinical outcomes provided facevalidity 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.
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, Consultant Musculoskeletal Radiologist North Bristol NHS Trust, who provided substantial training and expertise for this study. This work has been conducted using the UK Biobank resource (application number 17295). The authors would like to thank the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for
the Rotterdam Study (RSI, RSII, RSIII) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The authors would like to thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and 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. Mathijs Versteeg for creating the alpha angle data.
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, The genetic architecture of cam morphology 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)
- Genome Wide Association Studies,
- femoro-acetabular impingement
- alpha angle