A genome wide linkage scan of metacarpal size and geometry in the Framingham Study

Bone geometry is a significant component of bone strength, and has a clinical utility in predicting fractures and quantifying bone loss. Bone geometry is known to have a substantial genetic component. We performed linkage analysis to identify chromosomal regions governing metacarpal bone geometry. A genome-wide scan (with a set of 615 markers with spacing of approximately 5.7 cM) was performed on 1,702 individuals from 330 extended families of the Framingham Study. Midshaft width was measured and several indices calculated, namely Metacarpal Cortical Thickness (MCT), Cortical Index (MCI), and Section Modulus (MZ), using digitized X-rays of 1,380 participants (men, n = 666, mean age 55.2 yr, women, n = 714, 55.5 yr). Metacarpals 2, 3, and 4 were averaged. Heritability was significant for all indices, ranging from 0.51 to 0.72. Linkage analysis of indices adjusted for age, age(2), and estrogen status in women, identified chromosomal regions 6p21, 9p21, 11q21-q22, and Xq26-Xq27, with LOD scores >2.0. Additional adjustment for smoking, height, and BMI, generally reduced the LOD scores. Finally, bivariate linkage analysis confirmed that a QTL on chr. 6 (51 cM) was shared by midshaft width and MZ (LOD = 2.40, adjusted for all covariates). Neither MCT nor MCI shared linkage loci with width or MZ. In conclusion, we have identified chromosomal regions potentially linked to bone geometry. Genes in these regions may regulate bone geometry via effects on body size. Identification and subsequent characterization of loci for bone geometry can further elucidate the genetic contributions to bone's resistance to stress.