TY - JOUR
T1 - Multidimensional Bone Density Phenotyping Reveals New Insights Into Genetic Regulation of the Pediatric Skeleton
AU - Mitchell, Jonathan A.
AU - Chesi, Alessandra
AU - Cousminer, Diana L.
AU - McCormack, Shana E.
AU - Kalkwarf, Heidi J.
AU - Lappe, Joan M.
AU - Gilsanz, Vicente
AU - Oberfield, Sharon E.
AU - Shepherd, John A.
AU - Kelly, Andrea
AU - Zemel, Babette S.
AU - Grant, Struan F.A.
N1 - Funding Information:
The study was funded by NIH, National Heart, Lung, and Blood Institute (NHLBI) grant R01 HD58886; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts (N01-HD-1-3228, N01-HD-1-3329, N01-HD-1-3330, N01-HD-1-3331, N01-HD-1-3332, and N01-HD-1-3333); and the CTSA program Grant 8 UL1 TR000077. JM was supported by NIH, National Heart, Lung, and Blood Institute (NHLBI) grant K01 HL123612. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We appreciate the dedication of the study participants and their families, and the support of Dr. Karen Winer, Scientific Director of the Bone Mineral Density in Childhood Study.
Publisher Copyright:
© 2017 American Society for Bone and Mineral Research
PY - 2018/5
Y1 - 2018/5
N2 - Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci. However, this approach is limited because there is a degree of aBMD discordance across skeletal sites. We therefore applied a novel multidimensional phenotyping approach to further understand the genetic regulation of pediatric aBMD. Our sample comprised a prospective, longitudinal cohort of 1293 children of European ancestry (52% female; up to seven annual measurements). Principal components analysis was applied to dual-energy X-ray absorptiometry–derived aBMD Z-scores for total hip, femoral neck, spine, and distal radius to generate multidimensional aBMD phenotypes (ie, principal component scores). We tested the association between a genetic score (percentage of bone lowering alleles at 63 loci) and each principal component. We also performed a genomewide association study (GWAS) using the multiethnic baseline data (n = 1885) to identify novel loci associated with these principal components. The first component (PC1) reflected a concordant phenotypic model of the skeleton (eg, higher loading score = higher BMD across all sites). In contrast, PC2 was discordant for distal radius versus spine and hip aBMD, and PC3 was discordant for spine versus distal radius and hip aBMD. The genetic score was associated with PC1 (beta = –0.05, p = 3.9 × 10–10), but was not associated with discordant PC2 or PC3. Our GWAS discovered variation near CPED1 that associated with PC2 (rs67991850, p = 2.5 × 10–11) and near RAB11FIP5 (rs58649746, p = 4.8 × 10–9) that associated with PC3. In conclusion, an established bone fragility genetic summary score was associated with a concordant skeletal phenotype, but not discordant skeletal phenotypes. Novel associations were observed for the discordant multidimensional skeletal phenotypes that provide new biological insights into the developing skeleton.
AB - Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci. However, this approach is limited because there is a degree of aBMD discordance across skeletal sites. We therefore applied a novel multidimensional phenotyping approach to further understand the genetic regulation of pediatric aBMD. Our sample comprised a prospective, longitudinal cohort of 1293 children of European ancestry (52% female; up to seven annual measurements). Principal components analysis was applied to dual-energy X-ray absorptiometry–derived aBMD Z-scores for total hip, femoral neck, spine, and distal radius to generate multidimensional aBMD phenotypes (ie, principal component scores). We tested the association between a genetic score (percentage of bone lowering alleles at 63 loci) and each principal component. We also performed a genomewide association study (GWAS) using the multiethnic baseline data (n = 1885) to identify novel loci associated with these principal components. The first component (PC1) reflected a concordant phenotypic model of the skeleton (eg, higher loading score = higher BMD across all sites). In contrast, PC2 was discordant for distal radius versus spine and hip aBMD, and PC3 was discordant for spine versus distal radius and hip aBMD. The genetic score was associated with PC1 (beta = –0.05, p = 3.9 × 10–10), but was not associated with discordant PC2 or PC3. Our GWAS discovered variation near CPED1 that associated with PC2 (rs67991850, p = 2.5 × 10–11) and near RAB11FIP5 (rs58649746, p = 4.8 × 10–9) that associated with PC3. In conclusion, an established bone fragility genetic summary score was associated with a concordant skeletal phenotype, but not discordant skeletal phenotypes. Novel associations were observed for the discordant multidimensional skeletal phenotypes that provide new biological insights into the developing skeleton.
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U2 - 10.1002/jbmr.3362
DO - 10.1002/jbmr.3362
M3 - Article
C2 - 29240982
AN - SCOPUS:85044508655
VL - 33
SP - 812
EP - 821
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
SN - 0884-0431
IS - 5
ER -