An atlas of genetic influences on osteoporosis in humans and mice

Morris, John A.; Kemp, John P.; Youlten, Scott E.; Laurent, Laetitia; Logan, John G.; Chai, Ryan C.; Vulpescu, Nicholas A.; Forgetta, Vincenzo; Kleinman, Aaron; Mohanty, Sindhu T.; Sergio, C. Marcelo; Quinn, Julian; Nguyen-Yamamoto, Loan; Luco, Aimee-Lee; Vijay, Jinchu; Simon, Marie-Michelle; Pramatarova, Albena; Medina-Gomez, Carolina; Trajanoska, Katerina; Ghirardello, Elena J.; Butterfield, Natalie C.; Curry, Katharine F.; Leitch, Victoria D.; Sparkes, Penny C.; Adoum, Anne-Tounsia; Mannan, Naila S.; Komla-Ebri, Davide S. K.; Pollard, Andrea S.; Dewhurst, Hannah F.; Hassall, Thomas A. D.; Beltejar, Michael-John G.; 23andMe Research Team; Adams, Douglas J.; Vaillancourt, Suzanne M.; Kaptoge, Stephen; Baldock, Paul; Cooper, Cyrus; Reeve, Jonathan; Ntzani, Evangelia E.; Evangelou, Evangelos; Ohlsson, Claes; Karasik, David; Rivadeneira, Fernando; Kiel, Douglas P.; Tobias, Jonathan H.; Gregson, Celia L.; Harvey, Nicholas C.; Grundberg, Elin; Goltzman, David; Adams, David J.; Lelliott, Christopher J.; Hinds, David A.; Ackert-Bicknell, Cheryl L.; Hsu, Yi-Hsiang; Maurano, Matthew T.; Croucher, Peter I.; Williams, Graham R.; Bassett, J. H. Duncan; Evans, David M.; Richards, J. Brent

Affiliations

¹Department of Human Genetics, McGill University, Montréal, Québec, Canada.

²Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.

³University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.

⁴MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

⁵Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

⁶Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK.

⁷Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA.

⁸Department of Research, 23andMe, Inc., Mountain View, CA, USA.

⁹Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

¹⁰McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada.

¹¹Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

¹²Department of Biomedical Genetics, University of Rochester, Rochester, NY, USA.

¹³A list of members appears at the end of the paper.

¹⁴Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

¹⁵Department of Medicine, McGill University, Montréal, Québec, Canada.

¹⁶Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

¹⁷MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

¹⁸NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.

¹⁹NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.

²⁰Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.

²¹Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, RI, USA.

²²Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

²³Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden.

²⁴Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

²⁵Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

²⁶Department of Medicine, Harvard Medical School, Boston, MA, USA.

²⁷Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA.

²⁸Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK.

²⁹Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA.

³⁰Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.

³¹Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY, USA.

³²Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, Québec, Canada.

³³Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK.

Abstract

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10⁻⁷⁵) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

Links

DOI: 10.1038/s41588-018-0302-x

PubMed: 30598549

WoS: 000457314300012

History

Received: 2018-02-19

Accepted: 2018-11-05

Online: 2018-12-31

Cited Works (4)

Year	Entry
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