PuSH - Publication Server of Helmholtz Zentrum München: A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults.

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Faber, B.G.* ; Frysz, M.* ; Hartley, A.E.* ; Ebsim, R.* ; Boer, C.G.* ; Saunders, F.R.* ; Gregory, J.S.* ; Aspden, R.M.* ; Harvey, N.C.* ; Southam, L. ; Giles, W.* ; Le Maitre, C.L.* ; Wilkinson, J.M.* ; van Meurs, J.B.J.* ; Zeggini, E. ; Cootes, T.* ; Lindner, C.* ; Kemp, J.P.* ; Davey Smith, G.* ; Tobias, J.H.*

A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults.

Arthritis Rheum. 75, 900-909 (2023)

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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 (r_g =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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Femoroacetabular Impingement; Acetabular Dysplasia; Deformity

ISSN (print) / ISBN 0004-3591

e-ISSN 1529-0131

Journal Arthritis & Rheumatology

Quellenangaben Volume: 75, Issue: 6, Pages: 900-909

Publisher Wiley

Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Translational Genomics (ITG)

Grants Wellcome Trust
National Health and Medical Research Council (Australia)
Sir Henry Dale Fellowship - Royal Society
Sir Henry Dale Fellowship - Wellcome Trust
University Hospital Southampton
NIHR Southampton Biomedical Research Centre, University of Southampton
MRC
Medical Research Council (MRC) clinical research training fellowship