An atlas of genetic influences on osteoporosis in humans and mice
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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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The osteocyte transcriptome signature gene annotation explained ~12.5% (SE = 0.012, P = 1.6 × 10−7) of the total estimated SNP heritability of eBMD.
“and explained ~12.5% (SE = 0.012, P = 1.6 × 10−7) of the total estimated SNP heritability of eBMD (estimated previously25 at h2SNP = 0.36, SE = 0.017).”
From Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease (2021) · cites this paper as [25]
Eleven of the 26 knockout lines were in genes with established roles in the skeleton.
“Eleven were in genes with established roles in the skeleton, including Daam225 and Pls351.”
From Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease (2021) · cites this paper as [25]
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- Authors
- 23andMe Research Team, Morris, J. A., Kemp, J. P., Youlten, S. E., Laurent, L., Logan, J. G., Chai, R. C., Vulpescu, N. A., Forgetta, V., Kleinman, A., Mohanty, S. T., Sergio, C. M., Quinn, J., Nguyen-Yamamoto, L., Luco, A.-L., Vijay, J., Simon, M.-M., Pramatarova, A., Medina-Gomez, C., Trajanoska, K., Ghirardello, E. J., Butterfield, N. C., Curry, K. F., Leitch, V. D., Sparkes, P. C., Adoum, A.-T., Mannan, N. S., Komla-Ebri, D. S. K., Pollard, A. S., Dewhurst, H. F., Hassall, T. A. D., Beltejar, M.-J. G., Adams, D. J., Vaillancourt, S. M., Kaptoge, S., Baldock, P., Cooper, C., Reeve, J., Ntzani, E. E., Evangelou, E., Ohlsson, C., Karasik, D., Rivadeneira, F., Kiel, D. P., Tobias, J. H., Gregson, C. L., Harvey, N. C., Grundberg, E., Goltzman, D., Adams, D. J., Lelliott, C. J., Hinds, D. A., Ackert-Bicknell, C. L., Hsu, Y.-H., Maurano, M. T., Croucher, P. I., Williams, G. R., Bassett, J. H. D., Evans, D. M., & Richards, J. B.
- Affiliations
- Jewish General Hospital (CA)
- Translational Research Institute (AU)
- Garvan Institute of Medical Research (AU)
- Imperial College London (GB)
- NYU Langone Health (US)
- 23andMe (United States) (US)
- McGill University and Génome Québec Innovation Centre (CA)
- Erasmus MC (NL)
- University of Rochester Medicine (US)
- Wellcome Sanger Institute (GB)
- McGill University (CA)
- University of Cambridge (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- University of Oxford (GB)
- University of Ioannina (GR)
- University of Gothenburg (SE)
- Hebrew SeniorLife (US)
- Broad Institute (US)
- University of Bristol (GB)
- Children's Mercy Hospital (US)
- Research Institute of the McGill University Health Centre (CA)
- King's College London (GB)
- Corresponding author
- Evans, David M.
- Richards, J. Brent
- ORCID
- Morris, John A.
- Kemp, John P.
- Youlten, Scott E.
- Logan, John G.
- Chai, Ryan C.
- Vulpescu, Nicholas A.
- Forgetta, Vincenzo
- Mohanty, Sindhu T.
- Sergio, C. Marcelo
- Quinn, Julian
- Vijay, Jinchu
- Medina-Gomez, Carolina
- Trajanoska, Katerina
- Ghirardello, Elena J.
- Butterfield, Natalie C.
- Leitch, Victoria D.
- Sparkes, Penny C.
- Komla-Ebri, Davide S. K.
- Pollard, Andrea S.
- Dewhurst, Hannah F.
- Adams, Douglas J.
- Kaptoge, Stephen
- 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.
- Hsu, Yi-Hsiang
- Maurano, Matthew T.
- Croucher, Peter I.
- Williams, Graham R.
- Bassett, J. H. Duncan
- Evans, David M.
- Richards, J. Brent
- Venue
- Nature Genetics
- Published
- 2018-12-31
- Volume
- 51
- Issue
- 2
- Pages
- 258-266
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6358485
- OpenAlex
- W2904039649
- Cited by
- 773
- References
- 93
- Citations by year
- 2026: 64 · 2025: 98 · 2024: 115 · 2023: 115 · 2022: 99 · 2021: 112 · 2020: 113 · 2019: 54 · 2018: 1
- FWCI
- 76.85
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-04-15)
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Explore Bristol Research (acceptedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- Apollo
- Funders
- Ernest Heine Family Foundation
- Wellcome Trust (EU-FP7-, 101123, APP1137714, 20000, 201865, 094134)
- Australian Government
- National Institute for Health and Care Research (NF-SI-0617-10113, 10/33/04, APP1137714, HTA/10/33/04, NF-SI-0508-10082, NF-SI-0513-10085, NIHR-RP-R3-12-013)
- British Heart Foundation (RG/18/13/33946, RG/13/13/30194)
- King's College London
- European Commission (EU-FP7, 201865)
- Stiftelsen för Strategisk Forskning
- University of Queensland
- ZonMw (VIDI 016. 136. 361, ZonMw-VIDI 016.136.361, 016.136.361)
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Sahlgrenska Universitetssjukhuset
- Novo Nordisk Fonden (NNF14OC0010513, NNF18OC0033898, NNF13OC0005785)
- Versus Arthritis (20000, 21231, 17702)
- National Institutes of Health
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- Medical Research Council (MC_UU_12013, MC_UU_12013/4, MC_UU_12011/2, MC_UU_12011/1, EU FP7)
- Engineering and Physical Sciences Research Council (EP/J008192/1)
- National Health and Medical Research Council (1137714)
- Diamantina Institute, University of Queensland
- National Institute of General Medical Sciences (R35GM119703)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR060981, AR041398, R01AR072199, AR072199, R01AR070879, R01AR063702, R01AR041398)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- osteoporosis, bone mineral density, genome-wide association loci, bone fracture risk, knockout mice, chromatin accessibility, chromatin conformation, epigenomics, DAAM2, bone strength, age-related diseases, causal genes
- MeSH terms
- Adult, Aged, Animals, Female, Humans, Male, Middle Aged, Osteoporosis, Phenotype, Bone Density, Mice, Knockout, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Fractures, Bone, Mice, Genome-Wide Association Study
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