Bone Abstracts

Extreme high bone mass (HBM) may be monogenic (e.g. due to mutations in SOST or LRP5) or polygenic, due to variants in the same genes determining bone mineral density (BMD) as found in the general population. We aimed to determine the genetic cause underlying HBM in an extreme HBM population.

258 unexplained HBM cases (defined as L1 Z-score ≥+3.2 plus total hip Z-score ≥+1.2, or total hip Z-score ≥+3.2 and L1 Z-score ≥+1.2) were recruited from 15 UK centres, by screening 335, 115 DXA scans¹. Individuals with established SOST and LRP5 mutations were excluded by Sanger sequencing (n=3). We performed a GWAS for HBM, genotyping 240 HBM cases using Infinium OmniExpress-12v1.0 DNA analysis beadchips and clustering using GenomeStudio software (Illumina). Controls constituted two previously genotyped populations: i) unselected (n=5667, 1958 British Birth Cohort) and ii) ethnically-matched low BMD (n=900, Anglo-Australasian Osteoporosis Genetics Consortium² (AOGC) post-menopausal women with BMD Z-scores −4.0 to −1.5). Samples were assessed for cryptic relatedness, excess heterozygosity/missingness. SNPs with MAF<1%, and/or not in HWE were removed, leaving 181, 323 SNPs. The dataset was imputed using the 1000 Genomes Project; SNPs with r² threshold ≥0.8 were retained. SNPs were tested for association with BMD using PLINK, assessed separately for each control group. Results demonstrated over-representation of associations with BMD loci identified from the normal population³ (Figures 1 (HBM vs WTCCC) and 2 (HBM vs low AOGC)). Over-representation was greater when HBM was compared against the extreme low BMD population than when analysed against the unselected population, despite the larger population used in the latter analysis.

Extreme HBM cases are more likely to be polygenic in origin and controlled by the same genes that determine BMD in the general population. Studying extreme populations will enhance the discovery of such genes determining BMD. Whole-exome sequencing of our HBM population is underway to determine the exact variants contributing to HBM.

Figure 1 HBM cases vs unselected controls (1958 British Birth Cohort).

Figure 2 HBM cases vs low BMD controls (AOGC).