Using Mendelian randomization to investigate a possible causal relationship between adiposity and increased bone mineral density at different skeletal sites in children

Kemp, John P., Sayers, Adrian, Smith, George Davey, Tobias, Jonathan H. and Evans, David M. (2016) Using Mendelian randomization to investigate a possible causal relationship between adiposity and increased bone mineral density at different skeletal sites in children. International Journal of Epidemiology, 45 5: 1560-1572. doi:10.1093/ije/dyw079


Author Kemp, John P.
Sayers, Adrian
Smith, George Davey
Tobias, Jonathan H.
Evans, David M.
Title Using Mendelian randomization to investigate a possible causal relationship between adiposity and increased bone mineral density at different skeletal sites in children
Journal name International Journal of Epidemiology   Check publisher's open access policy
ISSN 0300-5771
1464-3685
Publication date 2016-10-01
Sub-type Article (original research)
DOI 10.1093/ije/dyw079
Open Access Status Not yet assessed
Volume 45
Issue 5
Start page 1560
End page 1572
Total pages 13
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2017
Language eng
Formatted abstract
Background: Lean 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.
Methods: To 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.
Results: Observationally, 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.
Conclusions: Our 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.
Keyword Bone
Body mass index
Genetics
Mendelian randomization
ALSPAC
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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Created: Fri, 21 Apr 2017, 11:07:30 EST by Kylie Hengst on behalf of Research Strategy and Support (Medicine)