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An atlas of genetic influences on osteoporosis in humans and mice

An atlas of genetic influences on osteoporosis in humans and mice
An atlas of genetic influences on osteoporosis in humans and mice
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.
1061-4036
Morris, John A.
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Kemp, John P
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Youlten, Scott E.
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Logan, John G.
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Chai, Ryan
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Vulpescu, Nicholas A
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Forgetta, Vincenzo
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Mohanty, Sindhu
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Sergio, C Marcelo
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Quinn, Julian
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Nguyen-Yamamoto, Loan
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Vijay, Jinchu
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Simon, Marie-Michelle
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Pollard, Andrea S.
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Richards, J. Brent
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Morris, John A., Kemp, John P, Youlten, Scott E., Laurent, Laetitia, Logan, John G., Chai, Ryan, Vulpescu, Nicholas A, Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu, 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., Konla-Ebri, Davide, Pollard, Andrea S., Dewhurst, Hannah F., Hassell, Thomas, Beltajar, Michael-John G., Adams, Douglas J., Vaillancourt, Suzanne M., Kaptoge, Stephen K., Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia, Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas R., Tobias, Jonathan H., Gregson, Celia L., Harvey, Nicholas, 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. and Richards, J. Brent (2018) An atlas of genetic influences on osteoporosis in humans and mice. Nature Genetics. (doi:10.1038/s41588-018-0302-x).

Record type: Article

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.

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Accepted/In Press date: 5 November 2018
e-pub ahead of print date: 31 December 2018

Identifiers

Local EPrints ID: 427202
URI: https://eprints.soton.ac.uk/id/eprint/427202
ISSN: 1061-4036
PURE UUID: fc684381-0091-45a4-a805-51a998374285
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Nicholas Harvey: ORCID iD orcid.org/0000-0002-8194-2512

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Date deposited: 07 Jan 2019 17:30
Last modified: 03 Dec 2019 05:08

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Contributors

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

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