Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential Pleiotropic effects on bone

Paternoster, Lavinia, Lorentzon, Mattias, Vandenput, Liesbeth, Karlsson, Magnus K., Ljunggren, Osten, Kindmark, Andreas, Mellstrom, Dan, Kemp, John P., Jarett, Caroline E., Holly, Jeff M. P., Sayers, Adrian, St. Pourcain, Beate, Timpson, Nicholas J., Deloukas, Panos, Smith, George Davey, Ring, Ssusan M., Evans, David M., Tobias, Jon H. and Ohlsson, Claes (2010) Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential Pleiotropic effects on bone. PLoS Genetics, 6 11: e1001217.1-e1001217.12. doi:10.1371/journal.pgen.1001217


Author Paternoster, Lavinia
Lorentzon, Mattias
Vandenput, Liesbeth
Karlsson, Magnus K.
Ljunggren, Osten
Kindmark, Andreas
Mellstrom, Dan
Kemp, John P.
Jarett, Caroline E.
Holly, Jeff M. P.
Sayers, Adrian
St. Pourcain, Beate
Timpson, Nicholas J.
Deloukas, Panos
Smith, George Davey
Ring, Ssusan M.
Evans, David M.
Tobias, Jon H.
Ohlsson, Claes
Title Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential Pleiotropic effects on bone
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2010-01-01
Year available 2010
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1001217
Open Access Status DOI
Volume 6
Issue 11
Start page e1001217.1
End page e1001217.12
Total pages 12
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Language eng
Subject 1311 Genetics
1312 Molecular Biology
1105 Dentistry
1306 Cancer Research
2716 Genetics (clinical)
Abstract 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 BMD C 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 BMD C 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/cm 3 per C allele, p = 2×10 -6; females -2.79 mg/cm 3 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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