Bone Abstracts

In previous work we identified 63 common variants (MAF>5%) from 56 loci associated with BMD fully comprising non-coding regions of the genome. We hypothesized that genes may harbour both common and rare variants in the protein-coding regions may influence BMD variation. The availability of the ‘exome-chip’ with 235 933 protein-coding variants (non-synonymous, splice sites and stop-altering) provides a feasible way to identify low-frequency variants in exomes.

We conducted an exome-chip meta-analysis for BMD to scrutinize coding variants for association with BMD. Up to 27 339 participants from 16 studies were genotyped using the exome-chip. BMD at the lumbar spine (LS) and femoral neck (FN) was measured by DXA. We performed regression analyses using an additive genetic-effect model in each study adjusting for age, age², sex, weight and ancestral genetic background. Gender-specific analyses were done for markers on the X-chromosome. An inverse-variance fixed-effect meta-analysis of 79 982 polymorphic variants (minor allele count ≥3) was conducted. Exome-chip significance threshold was set at 2.1×10⁻⁷.

The most significant association was found for a non-synonymous SNP V667M mapping to the LRP5 gene (MAF=5.3%, P=2×10⁻¹⁰ with LS BMD) among 61 other significant variants in known loci. Also two novel associations of non-synonymous variants with LS-BMD included: 3p21.31 harbouring A3863T in the BSN gene, MAF=46%, P_{meta_all}=3.8×10⁻⁸ and Xq22.2 harbouring P335S in the GLRA4 gene, MAF=0.6%, P_{meta_males}=1.9×10⁻⁷. The bassoon presynaptic cytomatrix protein (BSN) has unknown relation to bone biology. Males carrying the P335S variant in the glycine receptor, alpha 4 (GLRA4) had in average 0.5 standard deviations higher BMD at the LS compared to non-carriers in our studies.

In summary, we identified two novel loci carrying both common and rare non-synonymous variants associated with BMD. Better understanding of the mechanisms by which P335S GLRA4 increases BMD could lead into novel therapies for the treatment of osteoporosis in males.