Dataset Information

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

ABSTRACT:

Context

Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied.

Objective

We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children.

Methods

We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4-19 years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry.

Results

Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 × 10^-⁹). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score > 3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P = 4.6 × 10^-⁸), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 × 10^-⁸). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P < 9 × 10^-⁷).

Conclusions

We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.

SUBMITTER: Hou R

PROVIDER: S-EPMC7120871 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

Hou Ruixue R Cole Shelley A SA Graff Mariaelisa M Haack Karin K Laston Sandra S Comuzzie Anthony G AG Mehta Nitesh R NR Ryan Kathleen K Cousminer Diana L DL Zemel Babette S BS Grant Struan F A SFA Mitchell Braxton D BD Shypailo Roman J RJ Gourlay Margaret L ML North Kari E KE Butte Nancy F NF Voruganti V Saroja VS

Bone 20191129

<h4>Context</h4>Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied.<h4>Objective</h4>We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children.<h4>Methods</h4>We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva L ...[more]

PMID: 31790847

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Project description:BackgroundLean mass is positively associated with bone mineral density (BMD). However, the relationship between adiposity and BMD is more controversial. In particular, it is unclear if the observational association between the two reflects a causal effect of fat mass on BMD. Previous Mendelian randomization (MR) studies using variants in the FTO and MC4R genes as genetic instruments for adiposity have suggested that fat mass does indeed causally influence BMD. However, it is possible that these genetic variants pleiotropically influence lean mass and affect BMD through pathways independent of adiposity, invalidating one of the core assumptions of MR and complicating interpretation of the analysis.MethodsTo investigate whether adiposity causally affects BMD, we investigated the relationship between fat mass and BMD at the skull (SK), upper limbs (UL) and lower limbs (LL), spine (SP) and pelvis (PE), using 32 body mass index (BMI)-associated SNPs, including a variant near ADCY3 that was strongly associated with fat but not lean mass in our sample. Dual-energy X-ray absorptiometry (DXA) scans and genetic data were available for 5221 subjects (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children. We performed a series of MR analyses involving single BMI-associated SNPs and allelic scores of these SNPs. We used new extensions of the MR method including MR Egger regression and multivariable MR, which are more robust to possible confounding effects due to horizontal pleiotropy and, in the case of multivariable MR, specifically account for the effect of lean mass in the analysis. Bidirectional Mendelian randomization analysis was also performed to examine whether BMD causally affected BMI and adiposity.ResultsObservationally, fat mass was strongly positively related to BMD at all sites, but more weakly at the skull. Instrumental variables (IV) analyses using an allelic score of BMI SNPs suggested that fat mass was causally related to LL-BMD, UL-BMD, SP-BMD and PE-BMD but not SK-BMD. Multivariable MR, Egger regression and IV analyses involving the ADCY3 variant suggested a positive causal effect of adiposity on all sites except the skull, and that an effect was present even after taking lean mass into account. Finally, IV analyses using BMD allelic scores showed no evidence of reverse causality between BMD and fat mass.ConclusionsOur results suggest that adiposity is causally related to increased BMD at all sites except the skull, perhaps reflecting positive effects of loading on bone formation at weighted but not unweighted sites. In contrast, we found no evidence for BMD causally affecting BMI or measures of adiposity. Our results illustrate how MR can be used profitably to investigate clinical questions relevant to osteoporosis.

Dataset Information

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

Context

Objective

Methods

Results

Conclusions

Publications

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

Similar Datasets

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