Bivariate genome-wide linkage analysis of femoral bone traits and leg lean mass: Framingham study

The risk of osteoporotic fracture is a function of both applied muscle mass and bone tissue distribution. Leg lean mass (LLM) and femoral bone geometry are both known to have substantial genetic components. Therefore, we estimated shared heritability (h(2)) and performed linkage analysis to identify chromosomal regions governing both LLM and bone geometry. A genome-wide scan (using 636 microsatellite markers) for linkage analyses was performed on 1346 adults from 327 extended families of the Framingham study. DXA measures were LLM, femoral neck length, neck-shaft angle (NSA), subperiosteal width, cross-sectional area (CSA), and section modulus (Z) at the femoral narrow neck and shaft (S) regions. Variance component linkage analysis was performed on normalized residuals (adjusted for age, height, BMI, and estrogen status in women). The results indicated substantial h(2) for LLM (0.42 +/- 0.07) that was comparable to bone geometry traits. Phenotypic correlations between LLM and bone geometry phenotypes ranged from 0.033 with NSA (p > 0.05) to 0.251 with S_Z (p < 0.001); genetic correlations ranged from 0.087 (NSA, p > 0.05) to 0.454 (S_Z, p < 0.001). Univariate linkage analysis of covariate-adjusted LLM identified no chromosomal regions with LOD scores >or=2.0; however, bivariate analysis identified two loci with LOD scores >3.0, shared by LLM with S_CSA on chromosome 12p12.3-12p13.2, and with NSA, on 14q21.3-22.1. In conclusion, we identified chromosomal regions potentially linked to both LLM and femoral bone geometry. Identification and subsequent characterization of these shared loci may further elucidate the genetic contributions to both osteoporosis and sarcopenia.