F. Rivadeneira, U. Styrkarsdottir, M. Zillikens, B. Halldorsson, Y. Hsu, B. Richards, K. Estrada, F. Kavvoura, E. Grundberg, D. Karasik, T. Pastinen, S. Ralston, C. van Duijn, T. Spector, D. Kiel, U. Thorsteinsdottir, J. Ioannidis, A. Uitterlinden, I. GEFOS consortium

Introduction: Bone mineral density (BMD) is a highly heritable complex trait used to diagnose osteoporosis and assess fracture risk. Increased body weight is associated with increased BMD.

Aim: We performed meta-analysis of five genome-wide association studies on femoral neck (FN) and lumbar spine (LS) BMD in 19,195 Caucasian subjects of European origin and examined the relations with body weight.

Methods: Participants were drawn from the Rotterdam (n=4987;NL; Illumina550), ERF (n=1228;NL; Illumina317), Twins UK (n=2734 women;UK;Illumina317), deCODE (n=6743;IS; Illumina317), Framingham (n=3595;US;Affymetrix500) studies. We analyzed 2,543,686 SNPs imputed with reference to the HapMap CEU panel.

Results: One of the 20 loci identified as associated with BMD at genome-wide significant  (GWS, p<5x10^-8) level includes chromosome 11p15. The top SNP in the region was associated with femoral neck BMD at a GWS level only when adjusting for body weight, (the A allele increased BMD by  +0.09 SD, P= 6.4x10^-10). In an analysis not adjusting the BMD for weight the effect was 23% lower (+0.07 SD, P=3.1x10^-7). The A allele of this SNP was associated with a decrease of 0.6 kg in body weight per copy of the allele in the Rotterdam Study. The closest gene in the region is a transcription factor, part of the conserved high mobility group (HMG) DNA binding domain. The gene is expressed in a wide variety of tissues, most abundantly in skeletal muscle and is a good candidate for BMD determination. No correlation between the SNP and gene expression was observed in human osteoblast lineages. In lymphoblasts, a SNP in high LD (r²=0.95) with the top SNP was associated with expression levels of mRNA levels of NUCB2 (p=9.0x10^-4). NUCB2 codes for nesfatin-1, a highly conserved satiety molecule that is associated with melanocortin signaling in the appetite control hypothalamic nuclei in rats.

Conclusion: The A allele of a SNP on 11p15, identified through association with FN-BMD in a meta-analysis of five GWA studies, was associated with an increase in BMD and a decrease in body weight. This region may influence BMD through direct effect on lean mass, while simultaneously regulating food intake by influencing satiety. The compound analysis of expression and genome-wide association allowed us to identify a potential regulatory mechanisms explaining the observed paradoxical inverse relation of this SNP with BMD and body weight.

Disclosures: U. Styrkarsdottir, deCODE Genetics: Stock Options or Bond Holdings. U. Thorsteinsdottir, deCODE Genetics: Stock Options or Bond Holdings. B. Halldorsson, deCODE Genetics: Stock Options or Bond Holdings.