Femoral Neck Width Genetic Risk Score is A Novel Independent Risk Factor for Hip Fractures

Femoral neck width (FNW) derived from dual energy X-ray absorptiometry (DXA) scans may provide a useful adjunct to hip fracture prediction, by providing depth information missing from bone mineral density (BMD) measurements. Therefore, we investigated whether FNW is related to hip fracture risk independently of 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 years, 48.0% males) in UK Biobank (UKB). 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 signalling genes (MAGMA gene set analyses). FNW and FN-BMD SNPs were used to generate genetic instruments for multivariable Mendelian randomisation (MVMR). Greater genetically determined FNW increased risk of all hip fractures (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 four 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=338742, 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 (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.