Jonathan H Tobias

A common variant of HMGA2 is associated with adult and childhood height in the general population

Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10−8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10−11, overall P = 4 × 10−16, including the genome-wide association data). We also observed the association in children (P = 1 × 10−6, N = 6,827) and a tall/short case-control study (P = 4 × 10−6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

Association Between Bone Density and Fractures in Children: A Systematic Review and Meta-analysis

OBJECTIVE. The objective of this article was to systematically review all published studies that investigated the association between bone density and fractures in children. DESIGN. Potentially relevant articles were identified by searching electronic databases. Duplicates were removed, abstracts were inspected, and relevant articles were obtained. Studies were included in the systematic review if participants were <16.0 years old, were healthy, had extractable data on bone mass, and had fractures as the outcome. RESULTS. Ten case-control studies were identified. No prospective studies were found. There was no evidence of heterogeneity between studies or of funnel-plot asymmetry. Eight of the studies were included in the meta-analysis, because they presented results as means and standard deviations of bone density in cases and controls. The pooled standardized mean difference for bone mass in children with and without fractures, from a fixed-effects model, was −0.32 (95% confidence interval: −0.43 to −0.21). CONCLUSIONS. Evidence for an association between bone density and fractures in children is limited. The results from this meta-analysis suggest that there is an association between low bone density and fractures in children. Although there was no evidence of heterogeneity or publication bias, this meta-analysis is based on case-control studies that are prone to bias. Large, well-conducted prospective cohort studies are required to confirm the association between bone density and fractures in children.

Vigorous Physical Activity Increases Fracture Risk in Children Irrespective of Bone Mass : A Prospective Study of the Independent Risk Factors for Fractures in Healthy Children

Low bone mass is a determinant of fractures in healthy children. Small studies provide limited evidence on the association between ethnicity, birth weight, family size, socioeconomic status, dietary calcium intake, or physical activity and fracture incidence. No studies have investigated whether these determinants of fracture risk act through affecting bone mass or through other mechanisms. The aim of this study was to use a population‐based birth cohort to confirm which variables are determinants of fracture risk and to further study which of these risk factors act independently of bone mass. Children from the Avon Longitudinal Study of Parents and Children have been followed up from birth to 11 yr of age. Maternal self‐reported data have been collected contemporaneously on early life factors, diet, puberty, and physical activity. These were linked to reported fractures between 9 and 11 yr of age. Multivariable logistic regression techniques were used to assess whether these potential determinants were independent of, or worked through, estimated volumetric BMD or estimated bone size relative to body size measured by total body DXA scan at 9.9 yr of age. A total of 2692 children had full data. One hundred ninety‐three (7.2%) reported at least one fracture over the 2‐yr follow‐up period. Children who reported daily or more episodes of vigorous physical activity had double the fracture risk compared with those children who reported less than four episodes per week (OR, 2.06; 95% CI, 1.21–1.76). No other independent determinants of fracture risk in healthy children were found. In conclusion, reported vigorous physical activity is an independent risk factor for childhood fracture risk. However, the interrelationship between physical activity, bone mass, and childhood fracture risk suggests that the higher bone mass associated with increased physical activity does not compensate for the risk caused by increased exposure to injuries.

Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus

To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1×10−11 observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ±500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6×10−31 and an effect size explaining between 0.6%–1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42×10−10) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9×10−16) and rs7801723 (P = 8.9×10−28), also mapping to C7orf58 (r2 = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life.

Estimated maternal ultraviolet B exposure levels in pregnancy influence skeletal development of the child

CONTEXT Relationships between vitamin D exposure of the mother in pregnancy and skeletal development of the child are poorly understood. OBJECTIVES Our objectives were to establish whether background UVB levels in the third trimester of pregnancy are related to bone mineral content (BMC) of the child, and to examine whether these relationships are explained by effects on height, fat, or lean mass. DESIGN This was a prospective cohort study. SETTING The Avon Longitudinal Study of Parents and Children, a population-based birth cohort, was studied. PARTICIPANTS A total of 6995 boys and girls with a mean age of 9.9 yr was studied. OUTCOME MEASURES Prespecified analyses of relationships between background UVB levels in the third trimester of pregnancy, and total body less head BMC, bone area (BA), bone mineral density, and area-adjusted BMC as measured by dual-energy x-ray absorptiometry scans at 9.9 yr were performed. RESULTS Maternal UVB exposure was positively related to BMC (g) [9.6 (5.3, 13.8)], BA (cm(2)) [8.1 (4.3, 11.9)], and bone mineral density (g/cm(-2)) [0.003 (0.001, 0.004)], but not area-adjusted BMC (g) [0.69 (-0.22, 1.56)], suggesting an effect on bone size. Both height-dependent (cm) [0.18 (0.03, 0.32)] and height-independent (cm(2)) [4.1, (2.0, 6.2)] effects contributed to this association between UVB and BA. Although maternal UVB exposure was also related to lean mass (g) [163 (89, 237)], a positive association between UVB and BA persisted after adjusting for both height and lean mass [2.8 (1.0, 4.6)]. CONCLUSIONS Maternal UVB exposure is related to bone size at age 9.9 yr independently of height and lean mass, suggesting that vitamin D status in pregnancy exerts direct effects on periosteal bone formation in subsequent childhood.

How does body fat influence bone mass in childhood? A Mendelian randomization approach.

Fat mass may be a causal determinant of bone mass, but the evidence is conflicting, possibly reflecting the influence of confounding factors. The recent identification of common genetic variants related to obesity in children provides an opportunity to implement a Mendelian randomization study of obesity and bone outcomes, which is less subject to confounding and several biases than conventional approaches. Genotyping was retrieved for variants of two loci reliably associated with adiposity (the fat mass and obesity‐related gene FTO and that upstream of the MC4R locus) within 7470 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had undergone total body DXA scans at a mean of 9.9 yr. Relationships between both fat mass/genotypes and bone measures were assessed in efforts to determine evidence of causality between adiposity and bone mass. In conventional tests of association, both with and without height adjustment, total fat mass was strongly related to total body, spinal, and upper and lower limb BMC (ratio of geometric means [RGM]: 1.118 [95% CI: 1.112, 1.123], 1.110 [95% CI: 1.102, 1.119], 1.101 [95% CI: 1.093, 1.108], 1.146 [95% CI: 1.143, 1.155]; p < 10−10 [adjusted for sex, height, and sitting height]). Equivalent or larger effects were obtained from instrumental variable (IV) regression including the same covariates (1.139 [95% CI: 1.064, 1.220], 1.090 [95% CI: 1.010, 1.177], 1.142 [95% CI: 1.049, 1.243], 1.176 [95% CI: 1.099, 1.257]; p = 0.0002, 0.03, 0.002, and 2.3−6 respectively). Similar results were obtained after adjusting for puberty, when truncal fat mass was used in place of total fat, and when bone area was used instead of bone mass. In analyses where total body BMC adjusted for bone area (BA) was the outcome (reflecting volumetric BMD), linear regression with fat mass showed evidence for association (1.004 [95% CI: 1.002, 1.007], p = 0.0001). IV regression also showed a positive effect (1.031 [95% CI: 1.000, 1.062], p = 0.05). When MC4R and FTO markers were used as instruments for fat mass, similar associations with BMC were seen to those with fat mass as measured by DXA. This suggests that fat mass is on the causal pathway for bone mass in children. In addition, both directly assessed and IV‐assessed relationships between fat mass and volumetric density showed evidence for positive effects, supporting a hypothesis that fat effects on bone mass are not entirely accounted for by association with overall bone size.

Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20–0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n∼9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10−37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10−14). In addition, we report a novel association between RIN3 (previously associated with Pagets disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10−10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

Bone Fragility Contributes to the Risk of Fracture in Children, Even After Moderate and Severe Trauma

We prospectively examined whether the relationship between skeletal fragility and fracture risk in children 9.9 ± 0.3 (SD) yr is affected by trauma level. Bone size relative to body size and humeral vBMD showed similar inverse relationships with fracture risk, irrespective of whether fractures followed slight or moderate/severe trauma.

Obesity is a risk factor for musculoskeletal pain in adolescents: findings from a population-based cohort.

Summary Obesity is associated with the occurrence and severity of several musculoskeletal pain phenotypes, including knee pain and chronic regional pain in adolescents. Abstract Obesity is a risk factor for fibromyalgia in adults, but whether a similar relationship exists in children is uncertain. This study examined whether obesity is associated with reporting of musculoskeletal pain, including chronic regional pain (CRP) and chronic widespread pain (CWP), in adolescents, in a population‐based setting. A pain questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children at age 17, asking about site, duration, and pain intensity, from which participants with different types of musculoskeletal pain were identified. Relationships between obesity and pain were examined by calculating odds ratios stratified by gender and adjusted for socioeconomic status as reflected by level of maternal education. A total of 3376 participants (1424 boys) with complete data were identified, mean age 17.8; 44.7% of participants reported any pain within the last month lasting 1 day or longer; 16.3% reported lower back pain, 9.6% shoulder pain, 9.4% upper back pain, 8.9% neck pain, 8.7% knee pain, 6.8% ankle/foot pain, 4.7% CRP, and 4.3% CWP; 7.0% of participants were obese. Obesity was associated with increased odds of any pain (odds ratio [OR] 1.33, P = .04), CRP (OR 2.04, P = .005), and knee pain (OR 1.87, P = .001), but not CWP (OR 1.10, P = .5). Compared with non obese participants, those with any pain, knee pain, and CRP reported more severe average pain (P < .01). Obese adolescents were more likely to report musculoskeletal pain, including knee pain and CRP. Moreover, obese adolescents with knee pain and CRP had relatively high pain scores, suggesting a more severe phenotype with worse prognosis.

Fat mass exerts a greater effect on cortical bone mass in girls than boys.

CONTEXT It is unclear whether fat mass (FM) and lean mass (LM) differ in the way they influence cortical bone development in boys and girls. OBJECTIVE The aim of the study was to investigate the contributions of total body FM and LM to parameters related to cortical bone mass and geometry. DESIGN/SETTING We conducted a longitudinal birth cohort study, the Avon Longitudinal Study of Parents and Children. PARTICIPANTS A total of 4005 boys and girls (mean age, 15.5 yr) participated in the study. OUTCOME MEASURES We measured cortical bone mass, cortical bone mineral content (BMC(C)), cortical bone mineral density, periosteal circumference (PC), and endosteal circumference by tibial peripheral quantitative computed tomography. RESULTS LM had a similar positive association with BMC(C) in boys and girls [regression coefficients with 95% confidence interval (CI); P for gender interactions: boys/girls, 0.952 (0.908, 0.997); P = 0.85]. However, the mechanisms by which LM influenced bone mass differed according to gender because LM was positively associated with PC more strongly in girls [boys, 0.579 (0.522, 0.635); girls, 0.799 (0.722, 0.875); P < 0.0001], but was only associated with cortical bone mineral density in boys [boys, 0.443 (0.382, 0.505); girls, 0.014 (-0.070, 0.097); P < 0.0001]. There was a stronger positive association between FM and BMC(C) in girls [boys, 0.227 (0.185, 0.269); girls, 0.355 (0.319, 0.392); P < 0.0001]. This reflected both a greater positive association of FM with PC in girls [boys, 0.213 (0.174, 0.253); girls, 0.312 (0.278, 0.347); P = 0.0002], and a stronger negative association with endosteal circumference(PC) [boys, -0.059 (-0.096, 0.021); girls, -0.181 (-0.215, -0.146); P < 0.0001]. CONCLUSIONS Whereas LM stimulates the accrual of cortical bone mass to a similar extent in boys and girls, FM is a stronger stimulus for accrual of cortical bone mass in girls, reflecting a greater tendency in females for FM to stimulate periosteal growth and suppress endosteal expansion.