Fetal and childhood growth patterns associated with bone mass in school-age children: The generation R study

Low birth weight is associated with lower bone accrual in children and peak bone mass in adults. We assessed how different patterns of longitudinal fetal and early childhood growth influence bone properties at school age. In 5431 children participating in a population-based prospective cohort study, we measured fetal growth by ultrasound at 20 and 30 weeks gestation, and childhood growth at birth, 1, 2, 3, and 4 years of age. We analy

Genetic polymorphism of miR-196a-2 is associated with bone mineral density (BMD)

MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate the translation of messenger RNAs. Given the crucial role of miRNAs in gene expression, genetic variants within miRNA-related sequences may affect miRNA function and contribute to disease risk. Osteoporosis is characterized by reduced bone mass, and bone mineral density (BMD) is a major diagnostic proxy to assess osteoporosis risk. Here, we aimed to identify miRNAs that are involved in BMD using data from recent genome-wide association studies (GWAS) on femoral neck, lumbar spine and forearm BMD. Of 242 miRNA-variants available in the GWAS data, we found rs11614913:C > T in the precursor miR-196a-2 to be significantly associated with femoral neck-BMD (p-value = 9.9 × 10-7, β = −0.038) and lumbar spine-BMD (p-value = 3.2 × 10-11, β = −0.061). Furthermore, our sensitivity analyses using the Rotterdam study data showed a sex-specific association of rs11614913 with BMD only in women. Subsequently, we highlighted a number of miR-196a-2 target genes, expressed in bone and associated with BMD, that may mediate the miRNA function in BMD. Collectively, our results suggest that miR-196a-2 may contribute to variations in BMD level. Further biological investigations will give more insights into the mechanisms by which miR-196a-2 control expression of BMD-related genes

Ancestry and dental development: A geographic and genetic perspective

Objective: In this study, we investigated the influence of ancestry on dental development in the Generation R Study. Methods: Information on geographic ancestry was available in 3,600 children (1,810 boys and 1,790 girls, mean age 9.81±0.35 years) and information about genetic ancestry was available in 2,786 children (1,387 boys and 1,399 girls, mean age 9.82±0.34 years). Dental development was assessed in all children using the Demirjian method. The associations of geographic ancestry (Cape Verdean, Moroccan, Turkish, Dutch Antillean, Surinamese Creole and Surinamese Hindustani vs Dutch as the reference group) and genetic content of ancestry (European, African or Asian) with dental development was analyzed using linear regression models. Results: In a geographic perspective of ancestry, Moroccan (β=0.18; 95% CI: 0.07, 0.28), Turkish (β=0.22; 95% CI: 0.12, 0.32), Dutch Antillean (β=0.27; 95% CI: 0.12, 0.41), and Surinamese Creole (β=0.16; 95% CI: 0.03, 0.30) preceded Dutch children in dental development. Moreover, in a genetic perspective of ancestry, a higher proportion of European ancestry was associated with decelerated dental development (β=-0.32; 95% CI: -.44, -.20). In contrast, a higher proportion of African ancestry (β=0.29; 95% CI: 0.16, 0.43) and a higher proportion of Asian ancestry (β=0.28; 95% CI: 0.09, 0.48) were associated with accelerated dental development. When investigating only European children, these effect estimates increased to twice as large in absolute value. Conclusion: Based on a geographic and genetic perspective, differences in dental development exist in a population of heterogeneous ancestry and should be considered when describing the physiological growth in children

Infant dietary patterns and bone mass in childhood: the Generation R Study

Conclusions: An infant dietary pattern characterized by high intakes of dairy and cheese, whole grains, and eggs is positively associated with bone development in childhood. Further research is needed to investigate the consequences for bone health in later life.Results: Higher adherence score to a “dairy and whole grains” pattern was positively associated with BMD and aBMC, but not with BMC and BA. Accordingly, children in the highest quartile of the “dairy and whole grains” pattern had higher BMD (difference 3.98 mg/cm2, 95 % confidence interval (CI) 0.36 to 7.61) and aBMC (difference 4.96 g, 95 % CI 1.27 to 8.64) than children in the lowest quartile. Stratificati

Skeletal maturation in relation to ethnic background in children of school age: The Generation R Study

Ethnicity is a well-established determinant of pediatric maturity, but the underlying genetic and environmental contributions to these ethnic differences are poorly comprehended. We aimed to evaluate the influence of ethnicity on skeletal age (SA), an assessment of pediatric maturation widely used in clinical settings. We included children from the Generation R Study, a multiethnic population-based pregnancy cohort, assessed at a mean age of 9.78 (±0.33) years. SA was evaluated by a trained observer on hand DXA scans using the Greulich and Pyle method. Ethnic background was defined as geographic ancestry (questionnaire-based assessment) (N = 5325) and genetic ancestry (based on admixture analysis) (N = 3413). Associations between the ethnic background and SA were investigated separately in boys and girls, using linear regression models adjusted for age, height and BMI. Based on geographic ancestry, 84% of the children were classified as European, 6% as Asian and 10% as African. Children of European background had on average younger SA than those of Asian or African descent. Asian boys had 0.46 (95% CI 0.26–0.66, p-value < 0.0001) and African boys 0.36 years (95% CI 0.20–0.53, p-value < 0.0001) older SA as compared to European boys. Similarly, Asian girls showed 0.64 (95% CI 0.51–0.77, p-value < 0.0001) and African girls 0.38 years (95% CI 0.27–0.48, p-value < 0.0001) older SA as compared to European girls. A similar pattern was observed in the analysis with genetically-defined ancestry. Furthermore, an increase in the proportion of Asian or African component was associated with older SA in both boys (log[Non-European/European]proportion = 0.10, 95% CI 0.06–0.13, p-value < 0.0001) and girls (log[Non-European/European]proportion = 0.06, 95% CI 0.04–0.08, p-value < 0.0001). In summary, children of Asian and African backgrounds have on average older SA as compared to children of European descent, partially explained by a genetic com

BMD loci contribute to ethnic and developmental differences in skeletal fragility across populations: Assessment of evolutionary selection pressures

Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait

Improved imputation quality of low-frequency and rare variants in European samples using the 'Genome of the Netherlands'

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with 'true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05-0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r 2, increased from 0.61 to 0.71. W

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 fo

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sexspecific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N=15 661, with replication N=75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (b=0.06; P=0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population