Searchable abstracts of presentations at key conferences on calcified tissues
Bone Abstracts (2014) 3 OC4.3 | DOI: 10.1530/boneabs.3.OC4.3

ECTS2014 Oral Communications Genetics of bone disease (6 abstracts)

Exome-chip meta-analysis identifies novel associations of coding variants in BSN and GLRA4 with lumbar spine BMD in 27 339 adults of European descent

Karol Estrada 1 , Douglas Kiel 2 , Andre Uitterlinden 3 , Fernando Rivadeneira 3 , Yi-Hsiang Hsu 2 & for the exome-chip meta-analysis working group 1

25 views


1Massachusetts General Hospital, Boston, Massachusetts, USA; 2Hebrew SeniorLife, Boston, Massachusetts, USA; 3Erasmus Medical Center, Rotterdam, The Netherlands.


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.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

Browse other volumes

Article tools

My recent searches

No recent searches.