Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study
Introduction
The role of genetics in the acquisition of childhood bone mass is largely unknown. The phenotypic pattern of bone mass regulation over the life span, however, is well characterized. Bone accumulation dominates during childhood and peaks in early adulthood, while bone loss typically dominates later in life. Investigations of bone mass, both genetic and non-genetic, have traditionally focused on two definable aspects of this process; peak bone mass [21], [22], [44] and osteoporosis [3], [47], [48]. It is important to note that both are influenced by genetic and environmental factors, and their interactions, prior to the attainment of peak bone mass or onset of osteoporosis. Peak bone mass, for example, is the product of the genetic potential for bone accrual mediated by environmental factors from childhood through early adulthood, while the occurrence of osteoporosis is the result of the interaction between genes and environment on bone regulation subsequent to the attainment of peak bone mass.
Adult bone mass, primarily measured as bone mineral density (BMD), has typically been the focal phenotype in genetic studies of bone regulation in humans [6], [8], [9], [18], [29], [38], [39], [40]. With the growing awareness of the importance of childhood bone accrual in determining adult bone health status, however, genetic studies are emerging that incorporate children into the study design. Many of these employ the parent–offspring study design, comparing each generation at different points of the life span. Heritability estimates of bone mass in these studies range from 0.18 to 0.79, and tend to have large standard errors [13], [25].
Research using animal models, particularly rodents, has been successful in identifying a genetic component to bone growth and bone accrual. Knockout and transgenic mouse models have contributed significantly to knowledge of the effects of single genes in bone regulation, such as the insulin-like growth factor-1 and bone morphogenetic protein-4 genes [65], [66]. Highly inbred strains of mice provide a powerful means for investigating genetic influences over bone phenotypes [1], [5], [26], [31], [62]. A substantial genetic influence on peak bone mass has also been demonstrated by this study design [32], [45].
Bone mass measured during adulthood is a consequence of bone accrued during childhood and early adulthood, and any subsequent bone loss. Because bone accrual and loss each may have a unique genetic etiology, the study of genetic influences on adult bone mass ideally should take both processes into consideration. Bone mass measured during childhood represents only the amount of bone accrued up to that point in time, and should, therefore, be more proximal to genetic influences on bone accrual. Given the role of genetics in adult bone mass, and the difficulty involved in distinguishing between genes involved in bone acquisition versus bone loss, quantifying the heritability of bone mass in children provides important additional information for understanding the genetic architecture of bone accrual and maintenance.
In the current investigation, second metacarpal cortical bone thickness is used as a measure of childhood bone mass. Radiographic cortical bone thickness is a well-recognized valuable method for assessing bone biology, and has long been used as a measure of skeletal mass [4], [10], [12], [15], [16], [29], [30], [39], [40], [42]. Cortical thickness is measured as the amount of bone tissue present between the periosteal and endosteal surfaces. In metacarpals, the cortical thickness represents 90% of bone mineral contained in those bones [17]. Cortical measurements taken on a cylindrical bone such as the second metacarpal are generally more reliable than those taken from other bones [15]. Additionally, measures of cortical bone are less affected by short-term temporal fluctuation in bone mass caused by seasonal variation and weight changes than measures of bone mineral density or bone mineral content obtained from dual energy X-ray absorptiometry [29].
The aim of this paper is to estimate the narrow-sense heritability (additive genetic effect) of second metacarpal cortical bone mass after accounting for covariate effects, and examine genetic correlations between cortical bone mass and both skeletal maturation and bone size (i.e., bone length).
Section snippets
Study sample
Data for the current study were collected from participants of the Fels Longitudinal Study, the world's largest and longest-running longitudinal study of human growth, development, and body composition change over the life span [49]. The study sample for the current investigation is comprised of a subset of 600 participants (317 males, 283 females) in the Fels Longitudinal Study for whom hand-wrist radiographs were available at age 10 years. The 600 X-rays used in this study were taken between
Results
Descriptive statistics of the study sample, including sex-specific means and standard deviations for body measurements and radiographic measures of cortical bone mass, are shown in Table 2. Age, height, weight, BMI, skeletal age, and second metacarpal length were similar in both sexes. CI in females was slightly higher than in males, but cortical thickness measures and second metacarpal diameter tended to be higher in males. The sample-wide coefficients of variation ranged from 11.8 to 15.5%.
Discussion
The evidence for a significant role of genetics in determining adult bone mass is unequivocal. The extent to which bone mass in childhood is genetically influenced, however, is less well documented. Understanding the genetic influences on childhood bone mass is vital for understanding bone health and the etiology of diseases involving the regulation of bone mass. For instance, it has been demonstrated that genes influencing bone accrual directly affect peak bone mass, which is the strongest
Acknowledgments
We thank the participants in the Fels Longitudinal Study for their dedication to basic biomedical research. We thank Heather Broughton for assistance in radiographic measurements. And, we sincerely appreciate the helpful comments of the two anonymous reviewers of this paper. This work was supported by United States of America National Institutes of Health grants HD36342, HD12252, and AR052147.
References (66)
- et al.
Multipoint quantitative-trait linkage analysis in general pedigrees
Am. J. Hum. Genet.
(1998) - et al.
The radiological diagnosis of osteoporosis: a new approach
Clin. Radiol.
(1960) - et al.
Genetic variability in adult bone density among inbred strains of mice
Bone
(1996) - et al.
Method for measuring quantity of bone
Lancet
(1969) - et al.
Genotype-by-sex and environment-by-sex interactions influence variation in serum levels of bone-specific alkaline phosphatase in adult baboons (Papio hamadryas)
Bone
(2004) - et al.
Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the framingham study
Bone
(2003) - et al.
Heritability of calcaneal quantitative ultrasound measures in healthy adults from the Fels Longitudinal Study
Bone
(2004) - et al.
Evidence for common controls over inheritance of bone quantity and body size from segregation analysis in a pedigreed colony of nonhuman primates
Bone
(2001) - et al.
Quantitative genetic study of radiographic hand bone size and geometry
Bone
(2003) - et al.
Genetic and environmental determinants of bone mineral density in Mexican Americans: results from the San Antonio Family Osteoporosis Study
Bone
(2003)
Sex differences in bone mass acquisition during growth: the Fels Longitudinal Study
J. Clin. Densitom.
Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth
Bone
Rural versus nonrural differences in BMC, volumetric BMD, and bone size: a population-based cross-sectional study
Bone
Transgenically ectopic expression of Bmp4 to the Msx1 mutant dental mesenchyme restores downstream gene expression but represses Shh and Bmp2 in the enamel knot of wild type tooth germ
Mech. Dev.
Genetic variations in bone density, histomorphometry, and strength in mice
Calcif. Tissue Int.
Genetic determinants of bone mass
Horm. Res.
Heritability of bone mass: a longitudinal study in aging male twins
Am. J. Hum. Genet.
Genetic influence on birthweight and gestational length determined by studies in offspring of twins
Br. J. Genet.
Cortical index and size of hand bones: segregation analysis and linkage with the 11q12-13 segment
Med. Sci. Monit.
Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density
Ann. Hum. Genet.
Quantitative radiology: radiogrammetry of cortical bone
Br. J. Radiol.
Likelihood, expanded ed
Familial resemblance for bone mineral mass is expressed before puberty
J. Clin. Endocrinol. Metab.
Profile comparisons of physical growth for monozygotic and dizygotic twin pairs
Ann. Hum. Biol.
The earlier gain and the later loss of cortical bone
Bone measurement in the differential diagnosis of osteopenia and osteoporosis
Radiology
Comparison of cortical thickness and radiographic microdensitometry in the measurement of bone loss
Segregation analysis and variance components analysis of bone mineral density in healthy families
J. Bone Miner. Res.
A quantitative trait locus for normal variation in forearm bone mineral density in pedigreed baboons maps to the ortholog of human chromosome 11q
J. Clin. Endocrinol. Metab.
Peak bone mass
Osteoporos Int.
Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone mineral density
Osteoporos Int.
Genetic, common environment, and individual specific components of variance for bone mineral density in 10- to 26-year-old females: a twin study
Am. J. Epidemiol.
Rates of growth and loss of bone mineral in the spine and femoral neck in white females
Osteoporos Int.
Cited by (20)
The influence of age at menarche on cross-sectional geometry of bone in young adulthood
2012, BoneCitation Excerpt :The second metacarpal is the most cylindrical bone in the hand and can be assumed to have bone evenly distributed about its axis [3,37]. As it is free from weight-bearing stress that would influence bone morphology, it has been widely used in biomedical investigations of bone health [3,37–44]. The radiographs were digitized using a Vidar DosimetryPRO Advantage Radiographic Scanner, and analyzed with a dedicated image processing program written for this purpose in MatLab v.7.7.0.471 [45].
Cortical bone health shows significant linkage to chromosomes 2p, 3p, and 17q in 10-year-old children
2011, BoneCitation Excerpt :Quantitative measurements of bone mass from radiographs were obtained from the second metacarpal in each individual according to standard methods [29]. 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.
Cortical bone thickness at common miniscrew implant placement sites
2011, American Journal of Orthodontics and Dentofacial OrthopedicsCitation Excerpt :Schwartz-Dabney and Dechow22 also found no sex differences in cortical bone thickness for the mandible. The lack of sex differences in cortical bone thickness has also been reported for the second metacarpal, the proximal radius, and vertebral bodies.42-44 Since maximum bite force is not a regular or habitual function, like mastication, for example, it might not be expected to produce sex differences in cortical thickness.