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Meta-Analysis
. 2010 Nov 18;6(11):e1001217.
doi: 10.1371/journal.pgen.1001217.

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

Lavinia Paternoster  1 , Mattias Lorentzon, Liesbeth Vandenput, Magnus K Karlsson, Osten Ljunggren, Andreas Kindmark, Dan Mellstrom, John P Kemp, Caroline E Jarett, Jeff M P Holly, Adrian Sayers, Beate St Pourcain, Nicholas J Timpson, Panos Deloukas, George Davey Smith, Susan M Ring, David M Evans, Jon H Tobias, Claes Ohlsson
Affiliations
Meta-Analysis

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

Lavinia Paternoster et al. PLoS Genet. .

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 (BMD(C)) 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 BMD(C), 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 BMD(C) 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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Cartoon depicting different cortical dimensions derived from tibial pQCT scans.
Cortical bone mass is derived from the product of cortical bone area and cortical density.
Figure 2
Figure 2. QQ plot of the ALSPAC and GOOD genome-wide meta-analysis of BMDC.
Blue points show the full genome-wide results. Red points show the genome-wide results excluding the RANKL region (chr 13: 42000–42150Kb).
Figure 3
Figure 3. Manhattan plot of the ALSPAC and GOOD genome-wide meta-analysis of BMDC.
Figure 4
Figure 4. RANKL regional association plot of the ALSPAC and GOOD genome-wide meta-analysis of BMDC.
Diamonds show the ALSPAC and GOOD GWA meta-analysis p-values, with darker shades indicating increasing linkage disequilibrium with rs1021188. The triangle shows the meta-analysis p-value of all cohorts (discovery and replication) for rs1021188. The black square shows the second SNP in this region which we attempted to replicate in this study (rs9525613) and the black circle shows the p-value of rs9594738, which has previously been associated with areal bone mineral density (3). The grey line shows the recombination rate across the region (data from HapMap).
Figure 5
Figure 5. Mean (and standard error) BMDC z-scores per rs1021188 genotype in each of the cohorts.
Sample sizes are shown alongside each point. Diamonds show the combined z-score estimates per genotype (the width of the diamond represents the combined standard error).
Figure 6
Figure 6. Scatter plot and mean values of free plasma RANKL levels according to rs1021188 genotype.
Of the 37 subjects measured, replicate samples in six had a CV of >20% and were excluded, leaving 9, 17 and 5 samples with TT, CT and CC genotypes respectively (a single sample fell below the detection limit of the assay and was therefore entered at the lower detection value i.e 0.02pmol/l). A positive relationship was observed between number of minor rs1021188 alleles and plasma RANKL level (P = 0.005; linear regression analysis following Rank-Based Inverse Normal Transformation).
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