An atlas of genetic influences on osteoporosis in humans and mice

the 23 and Me Research Team, 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 TrajanoskaElena 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, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, Jennifer C. McCreight, Karen E. Huber, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Catherine H. Wilson, Cyrus Cooper, Jonathan H. Tobias, Celia L. Gregson, David J. Adams, David M. Evans

Research output: Contribution to journalArticle (Academic Journal)

102 Citations (Scopus)
226 Downloads (Pure)

Abstract

Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10-75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P < 0.0001). In-depth analysis of one such Target Gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.
Original languageEnglish
Pages (from-to)258–266
Number of pages15
JournalNature Genetics
Volume51
Early online date31 Dec 2018
DOIs
Publication statusPublished - Feb 2019

Fingerprint Dive into the research topics of 'An atlas of genetic influences on osteoporosis in humans and mice'. Together they form a unique fingerprint.

Cite this