Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham Study.

A genome-wide scan was performed in participants from the Framingham Osteoporosis Study (1557 members of 330 mostly Caucasian pedigrees), with 401 microsatellite markers spaced on average at 10 cM. Bone mineral density (BMD) was measured at the femoral neck, trochanter, Ward's area, and lumbar spine with DXA. Our recent study (J Bone Mines Res 17 (2002), 1718) reported a number of regions with suggestive linkage to possible quantitative trait loci (QTL). The current study estimates the heterogeneity of linkage in these regions in subsamples of our pedigrees, stratified on the known biological contributors to bone mass of sex, age, and body mass index (BMI). The pedigree sample was stratified into three sets of subgroups by sex [males (age range 35- 96 years), females (29-91 years)], by age [60 or younger (29-60 years) and older than 60 (61-96 years)], and by BMI [stratified into low or high BMI, by median cut-off 27.7 in males (BMI range 17-53) and 25.8 in females (14-54)]. Heritability estimates of BMD (adjusted for age, anthropometry, nutrition, physical activity, and, in females, estrogen use) in subsamples ranged from 0.47 to 0.69. Two-point and multipoint variance component linkage analyses of BMD (using SOLAR) in subsamples supported findings of previously reported suggestive linkage results in the total sample on 8q24.13 and 14q31 (LODs>2.0). However, heterogeneity of linkage was observed on 6p21.2 and 21qter, where findings in the total sample were not supported by subsamples. On the other hand, subsample-specific maxima were found, on 4q34.1 (males), 9q22-9q31 (younger), 16p13.2 (high BMI), and 17p13.3 (older), which were not reflected by the total sample results. In conclusion, heterogeneity of QTL effects was revealed in pedigree members stratified by sex, age, and BMI; in some instances new loci were identified in subgroups. These findings may suggest that effects of genes on the determination of BMD differ between men and women, younger and older, and lean and obese adults. Evaluation of family members stratified in homogeneous groups may be warranted in genetic studies of bone mass.