Genome-Wide Association Study of Heel Bone Mineral Density Identifies 153 Novel Loci and Implicates Functional Involvement of GPC6 in Osteoporosis

John A Morris1,2§, John P Kemp3,4§, Carolina Medina-Gomez5,6, Vincenzo Forgetta1, Nicole M Warrington3,7, Scott E Youlten8,9, Jie Zheng4, Celia L Gregson10, Elin Grundberg2, Katerina Trajanoska5,6, John G Logan11, Andrea S Pollard11, Penny C Sparks11, Elena J Ghirardello11, Rebecca Allen11, Victoria D Leitch11, Natalie C Butterfield11, Davide SK Komla-Ebri11, Anne-Tounsia Adoum11, Katharine F Curry11, Jacqueline K White12, Fiona Kussy12, Keelin Greenlaw1, ChangJiang Xu13, Nicholas C Harvey14, Cyrus Cooper14, David J Adams12, Celia MT Greenwood1,2,19,20, Matthew T Maurano15, Stephen Kaptoge16,22, Fernando Rivadeneira5,6, Jon H Tobias10, Peter I Croucher8,9,17, Cheryl L Ackert-Bicknell18, JH Duncan Bassett11, Graham R Williams11, J Brent Richards1,2,21#, David M Evans3,4#

1. Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Canada; 2. Department of Human Genetics, McGill University; 3. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia; 4. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; 5. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; 6. Department of Epidemiology, Erasmus Medical Center; 7. School of Women’s and Infants’ Health, The University of Western Australia, Perth, Australia; 8. Garvan Institute of Medical Research, Sydney, Australia; 9. St Vincent's Clinical School, University of New South Wales, Sydney; 10. Musculoskeletal Research Unit, University of Bristol; 11. Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK; 12. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; 13. Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto, Canada; 14. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; 15. Department of Pathology and Institute for Systems Genetics, New York University Langone Medical Center, New York, USA; 16. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 17. School of Biotechnology and Biomolecular Sciences, University of New South Wales; 18. Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, USA; 19. Gerald Bronfman Department of Oncology, McGill University; 20. Department of Epidemiology, Biostatistics & Occupational Health, McGill University; 21. Department of Twin Research and Genetic Epidemiology, King's College London, London; 22. Strangeways Research Laboratory, Worts’ Causeway, Cambridge

§, # These authors contributed equally


Bone mineral density (BMD) is a highly heritable trait that is used as the primary diagnostic and prognostic marker for osteoporosis and fracture risk susceptibility, and is conventionally measured at the hip or spine by dual energy X-ray absorptiometry. Quantitative ultrasound (QUS) is a non-invasive technique that measures the speed and attenuation of ultrasound through bone, and estimates bone mineral density (eBMD). Previous genome-wide association studies (GWAS) of BMD/QUS measures (N = 35,000) identified up to 68 loci but explained less than 5% of the trait heritability, therefore missing heritability could be explained by many loci remaining to be discovered at greater sample sizes.


To identify genetic loci associated with BMD variation, we undertook a GWAS of eBMD of the heel on 142,487 individuals of European decent (76,067 females and 66,420 males) from the UK Biobank Study. To investigate underlying mechanisms of genetic loci, we undertook: 1) bioinformatic, functional genomic annotation, and human osteoblast expression studies; 2) gene function prediction; 3) skeletal phenotyping of 120 knockout mice with deletions of genes proximal to the identified loci; and 4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts.


We identified 307 conditionally independent SNPs attaining genome-wide significance (P < 6.6x10-9) at 203 loci, explaining 11.8% of the phenotypic variance. These included 153 novel loci, and several rare variants with large effect sizes. Linkage disequilibrium score regression revealed genetic correlations between eBMD, BMD measures at other skeletal sites, and fracture. Our study of underlying mechanisms strongly implicated GPC6 as a novel determinant of BMD and also identified abnormal skeletal phenotypes in knockout mice for a further 100 prioritized genes.


Overall, we have almost tripled the number of BMD-associated loci, doubled the variance in BMD explained by genetic factors, and identified new potential drug targets for the prevention and treatment of osteoporosis that can be tested directly in disease models. This work is currently under review at Nature Genetics.