Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure

Paternoster, Lavinia, Lorentzon, Mattias, Lehtimaki, Terho, Eriksson, Joel, Kahonen, Mika, Raitakari, Olli, Laaksonen, Marika, Sievanen, Harri, Viikari, Jorma V, Lyytikainen, Leo-Pekka, Mellstrom, Dan, Karlsson, Magnus, Ljunggren, Osten, Grundberg, Elin, Kemp, John P., Sayers, Adrian, Nethander, Maria, Evans, David M., Vandenput, Liesbeth, Tobias, Jon H. and Ohlsson, Claes (2013) Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure. PLoS Genetics, 9 2: 1-15. doi:10.1371/journal.pgen.1003247


Author Paternoster, Lavinia
Lorentzon, Mattias
Lehtimaki, Terho
Eriksson, Joel
Kahonen, Mika
Raitakari, Olli
Laaksonen, Marika
Sievanen, Harri
Viikari, Jorma V
Lyytikainen, Leo-Pekka
Mellstrom, Dan
Karlsson, Magnus
Ljunggren, Osten
Grundberg, Elin
Kemp, John P.
Sayers, Adrian
Nethander, Maria
Evans, David M.
Vandenput, Liesbeth
Tobias, Jon H.
Ohlsson, Claes
Title Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
1553-7404
Publication date 2013-02
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1003247
Open Access Status DOI
Volume 9
Issue 2
Start page 1
End page 15
Total pages 15
Place of publication San Francisco, United States
Publisher Public Library of Science (PLoS)
Collection year 2014
Language eng
Formatted abstract
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10-14; LOC285735, rs271170, p = 2.7×10-12; OPG, rs7839059, p = 1.2×10-10; and ESR1/C6orf97, rs6909279, p = 1.1×10-9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10-9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ
Additional Notes Article number e1003247.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
UQ Diamantina Institute Publications
 
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