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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure
Paternoster, Lavinia Lorentzon, Mattias Lehtimäki, Terho Eriksson, Joel Kähönen, Mika Raitakari, Olli Laaksonen, Marika Sievänen, Harri Viikari, Jorma Lyytikäinen, Leo-Pekka
Paternoster, Lavinia
Lorentzon, Mattias
Lehtimäki, Terho
Eriksson, Joel
Kähönen, Mika
Raitakari, Olli
Laaksonen, Marika
Sievänen, Harri
Viikari, Jorma
Lyytikäinen, Leo-Pekka
Author
Paternoster, Lavinia
Lorentzon, Mattias
Lehtimäki, Terho
Eriksson, Joel
Kähönen, Mika
Raitakari, Olli
Laaksonen, Marika
Sievänen, Harri
Viikari, Jorma
Lyytikäinen, Leo-Pekka
Mellström, Dan
Karlsson, Magnus
Ljunggren, Östen
Grundberg, Elin
Kemp, John P.
Sayers, Adrian
Nethander, Maria
Evans, David M.
Vandenput, Liesbeth
Tobias, Jon H.
Ohlsson, Claes
Lorentzon, Mattias
Lehtimäki, Terho
Eriksson, Joel
Kähönen, Mika
Raitakari, Olli
Laaksonen, Marika
Sievänen, Harri
Viikari, Jorma
Lyytikäinen, Leo-Pekka
Mellström, Dan
Karlsson, Magnus
Ljunggren, Östen
Grundberg, Elin
Kemp, John P.
Sayers, Adrian
Nethander, Maria
Evans, David M.
Vandenput, Liesbeth
Tobias, Jon H.
Ohlsson, Claes
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.
Keywords
Date
2013
Type
Journal article
Journal
PLoS Genetics
Book
Volume
9
Issue
2
Page Range
1-15
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
Open access
License
CC BY 3.0
File Access
Open