Investigation of the genetic architecture of cam morphology, and its relationship with hip osteoarthritis, using alpha angle as a proxy measure

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, suggest that hip shape remodelling secondary to a genetic predisposition to HOA contribute to the well-established relationship between HOA and cam morphology in older adults.

Hip geometric parameters are associated with radiographic and clinical hip osteoarthritis: Findings from a cross-sectional study in UK Biobank

“…An alternative explanation is that the femoral neck is widened as part of, or in parallel to the onset of HOA rather than the widened femoral neck causing HOA. Recent evidence from studies using SSM suggests a wider femoral neck is associated with more severe HOA and separately a genetic study suggested that a genetic predisposition to HOA led to cam-like changes at the femoral head ( 11 , 26 , 27 ). Both these studies suggest that hip shape is associated with but might not be a cause of HOA which has treatment implications.…”

“…The strengths of this study include its large sample size obtained through novel automated measures which have facilitated the description of DXA-derived hip geometry in UK Biobank, including the derivation of DFH which is not provided by existing HSA software. A sample size of this magnitude paves the way for future use of genetic epidemiological methods, which can add further understanding of aetiology of hip shape and its role in the pathogenesis of HOA ( 26 , 35 ). In addition, this study showed how hip geometric measures are longitudinally associated with THR justifying further work to understand whether these measures could be combined with measures of DXA-derived radiographic HOA to better understand THR risk.…”

Hip geometric parameters are associated with radiographic and clinical hip osteoarthritis: findings from a cross-sectional study in UK Biobank

“…An alternative explanation is that the femoral neck is widened as part of, or in parallel to the onset of HOA rather than the widened femoral neck causing HOA. Recent evidence from studies using SSM suggests a wider femoral neck is associated with more severe HOA and separately a genetic study suggested that a genetic predisposition to HOA led to cam-like changes at the femoral head (11,26,27). Both these Hip geometry and its associations with hip osteoarthritis studies suggest that hip shape is associated with but might not be a cause of HOA which has treatment implications.…”

“…The strengths of this study include its large sample size obtained through novel automated measures which have facilitated the description of DXA-derived hip geometry in UKB, including the derivation of DFH which is not provided by existing HSA software. A sample Hip geometry and its associations with hip osteoarthritis size of this magnitude paves the way for future use of genetic epidemiological methods, which can add further understanding of aetiology of hip shape and its role in the pathogenesis of HOA (26,35). In addition, the use of DXA scans which require lower radiation exposure than Xrays makes them more desirable for screening (10,36).…”