Endocrine Abstracts (2011) 26 P517

Genome-wide association in the Rotterdam study implicates the 16q24 locus as determinant of osteoporotic vertebral fractures

H L D W Oei, K Estrada, M C Castano-Betancourt, M van der Klift, J M Kerkhof, A Hofman, H A P Pols, L Stolk, J B van Meurs, M C Zillikens, A G Uitterlinden & F Rivadeneira

Erasmus MC, Rotterdam, The Netherlands.

Risk for vertebral fractures (VFx), the most common osteoporotic fractures, is a heritable complex trait. No genome-wide association studies (GWAS) searching for genetic susceptibility factors for VFx have been reported. We performed a GWAS for VFx in a population-based study of Dutch elderly. Thoracolumbar spine radiographs were scored for osteoporotic VFx using the McCloskey/Kanis method. Genetic data was available in 329 VFx cases and 2666 controls. We tested 2 543 887 imputed (HapMap CEU release 22, build 36) SNPs using a logistic regression model (MACH2DAT) adjusted for age, sex, and admixture principal components. At a genome-wide significant α-level (GWS) of 5×10−8, the design has 0.80 power to detect risk effect sizes (OR) of 1.7 to 2.4 for minor allele frequencies (MAF) of 0.20 to 0.05, respectively. A SNP on chromosome 16q24 (MAF=0.10) was associated at GWS level (P=4.6×10−8) with an increased risk for VFx. Heterozygous carriers of the minor allele had 1.7-fold (95% CI: 1.3–2.2) and homozygous carriers 5.8-fold (95% CI: 2.6–12.6) increased risk compared to non-carriers. The VFx-associated SNP maps in a region previously found associated with lumbar spine BMD (LS-BMD) in a meta-analysis of 19 125 individuals, yet represents an independent signal from the reported BMD SNP (LD r2=0.002). The VFx-associated SNP was not associated with LS-BMD. FOXC2 is a strong candidate gene mapping ~200 kb upstream from the associated SNP. FOXC2 is a transcription factor essential for axial skeletogenesis in mice, highly expressed in human bone tissue and involved in osteoblast differentiation through activation of canonical Wnt-β-catenin signals. Inactivating mutations affecting the FOX gene cluster cause severe vertebral malformations in humans. In conclusion, our findings implicate the 16q24 locus as a strong determinant for osteoporotic VFx. Pleiotropic effects of FOXC2 are potentially driving these associations with LS-BMD and VFx. Replication within the GEFOS/GENOMOS consortia is currently underway to confirm this finding.