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

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.

SUBMITTER: Paternoster L

PROVIDER: S-EPMC2987837 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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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 L Lorentzon Mattias M Vandenput Liesbeth L Karlsson Magnus K MK Ljunggren Osten O Kindmark Andreas A Mellstrom Dan D Kemp John P JP Jarett Caroline E CE Holly Jeff M P JM Sayers Adrian A St Pourcain Beate B Timpson Nicholas J NJ Deloukas Panos P Davey Smith George G Ring Susan M SM Evans David M DM Tobias Jon H JH Ohlsson Claes C

PLoS genetics 20101118 11

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 to ...[more]

PMID: 21124946

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Project description:BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Dataset Information

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

Publications

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

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