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%, Pmeta_all=3.8×10−8 and Xq22.2 harbouring P335S in the GLRA4 gene, MAF=0.6%, Pmeta_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.
17 May 2014 - 20 May 2014