Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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 and Lyytikainen, Leo-Pekka , et al. (2013) In PLoS Genetics 9(2).
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 = 3.6x10(-14);... (More)
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 = 3.6x10(-14); LOC285735, rs271170, p = 2.7x10(-12); OPG, rs7839059, p = 1.2x10(-10); and ESR1/C6orf97, rs6909279, p = 1.1x10(-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 = 1.9x10(-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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
9
issue
2
article number
e1003247
publisher
Public Library of Science (PLoS)
external identifiers
  • wos:000315638300011
  • scopus:84874766546
  • pmid:23437003
ISSN
1553-7404
DOI
10.1371/journal.pgen.1003247
language
English
LU publication?
yes
id
895e794d-36a5-4799-9a1a-c784ee9866b8 (old id 3657948)
date added to LUP
2016-04-01 10:36:00
date last changed
2024-06-03 23:17:49
@article{895e794d-36a5-4799-9a1a-c784ee9866b8,
  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 = 3.6x10(-14); LOC285735, rs271170, p = 2.7x10(-12); OPG, rs7839059, p = 1.2x10(-10); and ESR1/C6orf97, rs6909279, p = 1.1x10(-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 = 1.9x10(-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.}},
  author       = {{Paternoster, Lavinia and Lorentzon, Mattias and Lehtimaki, Terho and Eriksson, Joel and Kahonen, Mika and Raitakari, Olli and Laaksonen, Marika and Sievanen, Harri and Viikari, Jorma and Lyytikainen, Leo-Pekka and Mellstrom, Dan and Karlsson, Magnus and Ljunggren, Osten and Grundberg, Elin and Kemp, John P. and Sayers, Adrian and Nethander, Maria and Evans, David M. and Vandenput, Liesbeth and Tobias, Jon H. and Ohlsson, Claes}},
  issn         = {{1553-7404}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Genetics}},
  title        = {{Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure}},
  url          = {{https://lup.lub.lu.se/search/files/1976130/4006981.pdf}},
  doi          = {{10.1371/journal.pgen.1003247}},
  volume       = {{9}},
  year         = {{2013}},
}