Human Molecular Genetics Advance Access published online on January 30, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp052
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Common variants in the region around Osterix are associated with bone mineral density and growth in childhood
1 MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol BS8 2BN, UK 2 Dept. of Clinical Science at North Bristol, University of Bristol, Bristol, BS10 5NB, UK 3 Department of Medicine, Jewish General Hospital, McGill University, Montreal, H3T 1E2, Canada 4 Dept of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK 5 Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK 6 University of Queensland Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Brisbane, 4102, Australia 7 University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, OX3 7LD, UK 8 Garvan Institute of Medical Research, Sydney, 2010, Australia 9 Menzies Research Institute, Hobart, 7000, Australia 10 Department of Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, Geelong, 3220, Australia 11 School of Medicine and Pharmacology, University of Western Australia, Perth, 6009, Australia 12 Departments of Medicine and Endocrinology, University of Melbourne, Melbourne, 3084 Australia 13 Biomedicum Helsinki, Research Program in Molecular Medicine, University of Helsinki, Finland 14 Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland 15 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
* Address Correspondence to: David M. Evans. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom Tel: +44 (0)117 3310094, Fax: +441173310123. Email: dave.evans{at}bristol.ac.uk
Received October 24, 2008; Revised January 26, 2009; Accepted January 26, 2009
Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD) we performed a genome-wide association study (GWAS) of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results to a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: p=5.8 x 10–4; Australia: p=3.7 x 10–4). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (p=9.9 x 10–11). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (p=5.4 x 10–5). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.
These authors contributed equally to this work