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An atlas of genetic influences on osteoporosis in humans and mice.

Journal article
Authors 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
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
Published in Nature genetics
Volume 51
Pages 258-266
ISSN 1546-1718
Publication year 2019
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 258-266
Language en
Links dx.doi.org/10.1038/s41588-018-0302-...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Endocrinology

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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