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Bone Abstracts (2013) 1 PP282 | DOI: 10.1530/boneabs.1.PP282

ECTS2013 Poster Presentations Genetics (17 abstracts)

Phenotypic dissection of bone mineral density facilitates the identification of skeletal site specificity on the genetic regulation of bone

John P Kemp 1, , Carolina Medina-Gomez 3, , Karol Estrada 3, , Denise Heppe 5 , Carola Zillikens 3 , Nicholas Timpson 1, , Beate Pourcain 1 , Susan Ring 1 , Albert Hofman 3 , Vincent V W Jaddoe 5 , George Davey Smith 1, , André G Uitterlinden 3, , Jonathan H Tobias 6 , Fernando Rivadeneira 1, & David M Evans 1,

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1School of Social and Community Medicine, MRC CAiTE Centre, University of Bristol, Bristol, UK; 2School of Social and Community Medicine, University of Bristol, Bristol, UK; 3Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; 4Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; 5The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; 6School of Clinical Sciences, University of Bristol, Bristol, The Netherlands, UK.


Heritability of bone mineral density (BMD) varies at skeletal sites, possibly reflecting different relative contributions of environmental and genetic influences. To quantify shared genetic influences across different sites, we estimated the genetic correlation of BMD at the upper limb (UL), lower limb (LL), and skull (S) obtained from whole body DXA scans, using bivariate genome-wide complex trait analysis (GCTA). The study (n=9395) combined data from the Avon Longitudinal Study of Parents and their Children (n=5299, mean age=9.9 years) and the Generation R study (n=4096, mean age=6.2 years). GCTA estimates indicated that LL- and UL-BMD shared a high proportion of common genetic architecture (rg=0.78), compared to UL- and S-BMD (rg=0.58) and LL and S-BMD (rg=0.43). To explore the basis for these differences, genome-wide association analyses (GWAS; with meta-analysis) were performed to identify genetic signals associated with specific skeletal regions. A novel variant was identified within the RIN3 gene, independent of that previously reported in association with BMD, which was specifically associated with LL-BMD (P<5×10−8). Several genetic variants previously reported to be associated with BMD differed in their associations with BMD at different sub-regions. Specifically, effect sizes of variants which were independent, but proximal, revealed considerable degrees of site specificity at the WNT16 (7q31.31) and CENPW (6q22.32) loci. WNT16: rs13223036 showed stronger associations with S-BMD (β=0.17, P=1.5×10−28) and UL-BMD (β=0.19, P=1.3×10−34) compared to LL-BMD (β=0.02, P=0.2); rs2908004 was more strongly associated with UL-BMD (β=0.18, P=1.4×10−32) compared to S-BMD (β=0.09, P=3.6×10−9) and LL-BMD (β=0.10, P=3×10−11). CENPW rs2130604 was associated with S-BMD (β=0.11, P=3.3×10−11) more strongly than with UL-BMD (β=0.04, P=0.02) and LL-BMD (β=0.02, P=0.28). Our results suggest that BMD at different skeletal sites are to a certain extent under distinct genetic influences. Allowing for these differences may help to uncover new genetic influences on BMD, by providing greater power due to stronger site specific genetic effects.

Volume 1

European Calcified Tissue Society Congress 2013

Lisbon, Portugal
18 May 2013 - 22 May 2013

European Calcified Tissue Society 

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