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Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the Locus and Potential Pleiotropic Effects on Bone


Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMDC) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMDC, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged ∼15 years and GOOD n = 935, aged ∼19 years), we attempted to replicate the BMDC associations that had p<1×10−5 in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMDC in all cohorts (overall p = 2×10−14, n = 5739). Each minor allele was associated with a decrease in BMDC of ∼0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males −6.77mg/cm3 per C allele, p = 2×10−6; females −2.79 mg/cm3 per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development.


Vyšlo v časopise: Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the Locus and Potential Pleiotropic Effects on Bone. PLoS Genet 6(11): e32767. doi:10.1371/journal.pgen.1001217
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001217

Souhrn

Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMDC) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMDC, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged ∼15 years and GOOD n = 935, aged ∼19 years), we attempted to replicate the BMDC associations that had p<1×10−5 in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMDC in all cohorts (overall p = 2×10−14, n = 5739). Each minor allele was associated with a decrease in BMDC of ∼0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males −6.77mg/cm3 per C allele, p = 2×10−6; females −2.79 mg/cm3 per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development.


Zdroje

1. RichardsJ

RivadeneiraF

InouyeM

PastinenT

SoranzoN

2008 Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371 1505 1512 Available: http://linkinghub.elsevier.com/retrieve/pii/S0140673608605991

2. RivadeneiraF

StyrkársdottirU

EstradaK

HalldórssonBV

HsuY

2009 Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41 1199 1208 Available: http://www.nature.com/doifinder/10.1038/ng.446

3. StyrkarsdottirU

HalldorssonBV

GretarsdottirS

GudbjartssonDF

WaltersGB

2008 Multiple genetic loci for bone mineral density and fractures. New Engl J Med 358 2355 2365 Available: http://www.ncbi.nlm.nih.gov/pubmed/18445777

4. StyrkarsdottirU

HalldorssonBV

GretarsdottirS

GudbjartssonDF

WaltersGB

2009 New sequence variants associated with bone mineral density. Nat Genet 41 15 17 Available: http://www.ncbi.nlm.nih.gov/pubmed/19079262

5. JohnellO

KanisJA

OdenA

JohanssonH

LaetCD

2005 Predictive Value of BMD for Hip and Other Fractures. J Bone Miner Res 20 1185 1194 doi:10.1359/JBMR.050304

6. BachrachL

2001 Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrin Met 12 22 28

7. TimpsonNJ

TobiasJH

RichardsJB

SoranzoN

DuncanEL

2009 Common variants in the region around Osterix are associated with bone mineral density and growth in childhood. Hum Mol Genet 18 1510 1517 Available: http://www.ncbi.nlm.nih.gov/pubmed/19181680

8. PaternosterL

OhlssonC

SayersA

VandenputL

LorentzonM

2010 OPG and RANK polymorphisms are both associated with cortical BMD: findings from a meta-analysis of the ALSPAC and GOOD cohorts. J Clin Endocrinol Metab 95 3940 3948 Available: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917784

9. BoyleWJ

SimonetWS

LaceyDL

2003 Osteoclast differentiation and activation. Nature 423 337 342 Available: http://www.nature.com/doifinder/10.1038/nature01658

10. SeemanE

DelmasP

2006 Bone Quality — The Material and Structural Basis of Bone Strength and Fragility. New Engl J Med 354 2250 2261

11. ZebazeRM

Ghasem-ZadehA

BohteA

Iuliano-BurnsS

MiramsM

2010 Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet 375 1729 1736 Available: http://www.ncbi.nlm.nih.gov/pubmed/20472174

12. CummingsSR

San MartinJ

McClungMR

SirisES

EastellR

2009 Denosumab for prevention of fractures in postmenopausal women with osteoporosis. New Engl J Med 361 756 765 Available: http://www.ncbi.nlm.nih.gov/pubmed/19671655

13. KostenuikPJ

NguyenHQ

McCabeJ

WarmingtonKS

KuraharaC

2009 Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 24 182 195

14. GoldingJ

PembreyM

JonesR

2001 ALSPAC-the avon longitudinal study of parents and children. I. study methodology. Paediatr Perinat Epidemiol 15 74 87 Available: http://www3.interscience.wiley.com/journal/118982396/abstract

15. JonesRW

RingS

TyfieldL

HamvasR

SimmonsH

2000 A new human genetic resource: a DNA bank established as part of the Avon longitudinal study of pregnancy and childhood (ALSPAC). Eur J Hum Genet 8 653 660 Available: http://www.ncbi.nlm.nih.gov/pubmed/10980570

16. LiY

AbecasisGR

2006 Mach 1.0: Rapid Haplotype Reconstruction and Missing Genotype Inference. Am J Hum Genet S79 2290

17. LorentzonM

MellströmD

OhlssonC

2005 Association of amount of physical activity with cortical bone size and trabecular volumetric BMD in young adult men: the GOOD study. J Bone Miner Res 20 1936 1943

18. LorentzonM

SwansonC

AnderssonN

MellströmD

OhlssonC

2005 Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study. J Bone Miner Res 20 1334 1341 Available: http://www3.interscience.wiley.com/journal/123197455/abstract

19. MellströmD

JohnellO

LjunggrenO

ErikssonA

LorentzonM

2006 Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res 21 529 535 Available: http://www.ncbi.nlm.nih.gov/pubmed/16598372

20. EstradaK

AbuseirisA

GrosveldFG

UitterlindenAG

KnochTA

2009 GRIMP: a web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data. Bioinformatics 25 2750 2752 Available: http://bioinformatics.oxfordjournals.org/cgi/content/abstract/25/20/2750

21. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 81 559 575 Available: http://pngu.mgh.harvard.edu/purcell/plink/

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Genetika Reprodukčná medicína

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PLOS Genetics


2010 Číslo 11
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