Proximal hip geometry is linked to several chromosomal regions: genome-wide linkage results from the Framingham Osteoporosis Study

Abstract

Introduction: Femoral geometry contributes to bone strength and predicts hip fracture risk. The purpose of this study was to evaluate heritability (h(2)) of geometric indices of the proximal hip and to perform whole-genome linkage analyses of these traits, adjusted for body size.

Methods: DXA scans of the proximal femur from 1473 members of 323 pedigrees (age range 31-96 years) from the population-based Framingham Osteoporosis Study were obtained. Using the hip structural analysis program, we measured femoral neck length (FNL, cm) and neck-shaft angle (NSA); subperiosteal width (WID, cm), cross-sectional area (CSA, cm(2)); and section modulus (Z, cm(3)) at the narrowest section of the neck (NN), intertrochanteric (IT) and femoral shaft (S) regions. Linkage analyses were performed for the above indices with a set of 636 markers using variance components maximum likelihood method.

Results: Substantial genetic influences were found for all geometric phenotypes, with h(2) values between 0.28 (NSA) and 0.70 (IT_WID). Adjustment for height and BMI did not alter h(2) of NSA and FNL but decreased h(2) of the cross-sectional indices. We obtained substantial linkage (multipoint LOD >3.0) for S_Z at 2p21 and 21q11 and S_WID at Xq25-q26. Inclusion of height and BMI as covariates resulted in much lower LOD scores for S_Z, whereas linkage signals for S_Z at 4q25, S_CSA at 4q32 and S_CSA and S_Z at 15q21 increased after the adjustment. Linkage of FNL at 1q and 13q, NSA at 2q and NN_WID at 16q did not change after the adjustment.

Conclusion: Suggestive linkages of bone geometric indices were found at 1q, 2p, 4q, 13q, 15q and Xq. The identification of significant linkage regions after adjustment for BMI and height may point to QTLs influencing femoral bone geometry independent of body size.

Figure 1

Hip image from a DXA scanner showing positions of thin analysis regions across the femur at the neck, intertrochanteric and shaft regions. On the left are shown typical bone mass profiles from a single line of pixels across the bone. Geometry measurements are averaged over 5 parallel lines ~1 mm apart at each region.

Figure 2. Multipoint linkage results

A. S_Z, Chromosome 2 B. S_CSA, Chromosome 4 C. NN_WID, Chromosome 16. Model 1 (solid line) and Model 2 (dashed line).

Figure 2. Multipoint linkage results

A. S_Z, Chromosome 2 B. S_CSA, Chromosome 4 C. NN_WID, Chromosome 16. Model 1 (solid line) and Model 2 (dashed line).

Figure 2. Multipoint linkage results

A. S_Z, Chromosome 2 B. S_CSA, Chromosome 4 C. NN_WID, Chromosome 16. Model 1 (solid line) and Model 2 (dashed line).

Figure 3. Single-point and multipoint linkage results for S_WID on chromosome X

Diamonds: Single-point LOD scores. Multipoint results shown for Model 1 (solid line) and Model 2 (dashed line).