Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study

Abstract

The genetic influences on bone mass likely change throughout the life span, but most genetic studies of bone mass regulation have focused on adults. There is, however, a growing awareness of the importance of genes influencing the acquisition of bone mass during childhood on lifelong bone health. The present investigation examines genetic influences on childhood bone mass by estimating the residual heritabilities of different measures of second metacarpal bone mass in a sample of 600 10-year-old participants from 144 families in the Fels Longitudinal Study. Bivariate quantitative genetic analyses were conducted to estimate genetic correlations between cortical bone mass measures, and measures of bone growth and development. Using a maximum likelihood-based variance components method for pedigree data, we found a residual heritability estimate of 0.71 for second metacarpal cortical index. Residual heritability estimates for individual measures of cortical bone (e.g., lateral cortical thickness, medial cortical thickness) ranged from 0.47 to 0.58, at this prepubertal childhood age. Low genetic correlations were found between cortical bone measures and both bone length and skeletal age. However, after Bonferonni adjustment for multiple testing, ρ G was not significantly different from 0 for any of these pairs of traits. Results of this investigation provide evidence of significant genetic control over bone mass largely independent of maturation while bones are actively growing and before rapid accrual of bone that typically occurs during puberty.

Variation in childhood skeletal robustness is an important determinant of cortical area in young adults

“…The lack of differences in body size parameters (weight, height, BMI) among robustness tertiles in the current study further suggested the biological processes regulating robustness are not easily related to those regulating body size. In fact, heritability estimates for metacarpal width are high, ranging from 64–72% after adjusting for cofactors such as sex, age, height, and weight [6, 15]. Prior work in inbred mouse strains identified quantitative trait loci (QTLs) harboring genes regulating bone length, periosteal circumference, and body weight individually, as well as QTLs harboring genes regulating the relationship among these traits [23].…”

Human biology at the interface of paediatrics: Measuring bone mineral accretion during childhood

“…Up to 60 -80% of the variability in osteoporosis risk is explained by heritable factors (Krall and Dawson-Hughes 1993;Heaney et al 2000;Mora and Gilsanz 2003). Familial resemblance of BMC is expressed prior to puberty (Ferrari et al 1998;Duren et al 2007). Differences between population ancestry groups further demonstrate the strong genetic basis of variability in bone density and are evident in childhood (Gilsanz et al 1991;McCormick et al 1991;Bachrach et al 1999).…”

Cortical bone health shows significant linkage to chromosomes 2p, 3p, and 17q in 10-year-old children

“…In doing so, we maximize the ability to detect genetic involvement in the study traits. Boys and girls were analyzed together in all genetic analyses (all bone measures were shown to have no significant differences between the sexes; Duren et al[9]).…”

“…Bone diameter, medial cortical thickness, lateral cortical thickness, and medullary diameter were each measured in millimeters on the second metacarpal (see Duren et al[9]). All measurements were taken directly from original radiographs using digital Mitutoyo calipers with direct computer input.…”

“…Two additional variables were derived from these measures: 1) total cortical thickness, calculated as the sum of medial and lateral cortex; and 2) cortical index (CI), calculated as total cortex/bone diameter [after 30]. Sample-wide coefficients of variation ranged from 11.8 to 15.5% [9]. …”