1. Publications

An Atlas of Genetic Influences on Osteoporosis in Humans and Mice

John A. Morris, John P. Kemp, Scott E. Youlten, Laetitia Laurent, John G. Logan, Ryan C. Chai, Nicholas A. Vulpescu, Vincenzo Forgetta, Aaron Kleinman, Sindhu T. Mohanty, C. Marcelo Sergio, Julian Quinn, Loan Nguyen-Yamamoto, Aimee-Lee Luco, Jinchu Vijay, Marie-Michelle Simon, Albena Pramatarova, Carolina Medina-Gomez, Katerina Trajanoska, Elena J. Ghirardello, Natalie C. Butterfield, Katharine F. Curry, Victoria D. Leitch, Penny C. Sparkes, Anne-Tounsia Adoum, Naila S. Mannan, Davide S. K. Komla-Ebri, Andrea S. Pollard, Hannah F. Dewhurst, Thomas A. D. Hassall, Michael-John G. Beltejar, 23andMe Research Team, Douglas J. Adams, Suzanne M. Vaillancourt, Stephen Kaptoge, Paul Baldock, Cyrus Cooper, Jonathan Reeve, Evangelia E. Ntzani, Evangelos Evangelou, Claes Ohlsson, David Karasik, Fernando Rivadeneira, Douglas P. Kiel, Jonathan H. Tobias, Celia L. Gregson, Nicholas C. Harvey, Elin Grundberg, David Goltzman, David J. Adams, Christopher J. Lelliott, David A. Hinds, Cheryl L. Ackert-Bicknell, Yi-Hsiang Hsu, Matthew T. Maurano, Peter I. Croucher, Graham R. Williams, J. H. Duncan Bassett, David M. Evans & J. Brent Richards.
Nature Genetics. 2018-12-31;51(2):258-266.
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.
Consortium data used in this publication
GSE120755