Femoral neck width genetic risk score is a novel independent risk factor for hip fractures

Abstract

Femoral neck width (FNW) derived from DXA scans may provide a useful adjunct to hip fracture prediction. Therefore, we investigated whether FNW is related to hip fracture risk independently of femoral neck bone mineral density (FN-BMD), using a genetic approach. FNW was derived from points automatically placed on the proximal femur using hip DXA scans from 38 150 individuals (mean age 63.8 yr, 48.0% males) in UK Biobank (UKB). Genome-wide association study (GWAS) identified 71 independent genome-wide significant FNW SNPs, comprising genes involved in cartilage differentiation, hedgehog, skeletal development, in contrast to SNPs identified by FN-BMD GWAS which primarily comprised runx1/Wnt signaling genes (MAGMA gene set analyses). FNW and FN-BMD SNPs were used to generate genetic instruments for multivariable Mendelian randomization. Greater genetically determined FNW increased risk of all hip fractures (odds ratio [OR] 1.53; 95% CI, 1.29-1.82 per SD increase) and femoral neck fractures (OR 1.58;1.30-1.92), but not trochanteric or forearm fractures. In contrast, greater genetically determined FN-BMD decreased fracture risk at all 4 sites. FNW and FN-BMD SNPs were also used to generate genetic risk scores (GRSs), which were examined in relation to incident hip fracture in UKB (excluding the FNW GWAS population; n = 338 742, 3222 cases) using a Cox proportional hazards model. FNW GRS was associated with increased risk of all incident hip fractures (HR 1.08;1.05-1.12) and femoral neck fractures (hazard ratio [HR] 1.10;1.06-1.15), but not trochanteric fractures, whereas FN-BMD GRS was associated with reduced risk of all hip fracture types. We conclude that the underlying biology regulating FNW and FN-BMD differs, and that DXA-derived FNW is causally related to hip fractures independently of FN-BMD, adding information beyond FN-BMD for hip fracture prediction. Hence, FNW derived from DXA analyses or a FNW GRS may contribute clinically useful information beyond FN-BMD for hip fracture prediction.

Keywords: BMD; DXA; genome-wide association study (GWAS); hip geometry.

Figure 1

Independent effects of genetically determined FNW and FN-BMD on fracture risk in UKB: MVMR analyses to estimate the effect of genetically determined FNW and femoral neck bone mineral density (FN-BMD) on the risk of hip fracture, FN fractures, trochanteric fractures, and forearm fractures in UKB. Both prevalent and incident fractures were included. OR and 95% CIs are given.

Figure 2

Associations for FNW GRS and FN-BMD GRS with incident fractures in UKB The effects are given as HRs per SD increase in GRS. All models were adjusted for sex and baseline age, except the sex stratified models where sex was not included as a covariate. Age stratification was based on the median age at hip fracture (71.7 yr). ^*Significant age interaction (P = 1.3 × 10^-4) for FNW GRS. ^**Significant age interaction (P = 1.9 × 10^-3) for FNW GRS.

Figure 3

Additive associations for binarized high risk FNW GRS and, binarized high risk FN-BMD GRS with fractures risk. Participants in UKB were divided into 4 different groups (no/no, yes/no, no/yes and yes/yes) based on their binarized FNW GRS and binarized FN-BMD GRS, using 3 different cut-off limits as definitions of high risk for the 2 GRS (50%, 25%, and 10 %).