期刊
NATURE GENETICS
卷 51, 期 2, 页码 258-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0302-x
关键词
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资金
- Canadian Institutes of Health Research
- Canadian Foundation for Innovation
- Fonds de Recherche Sante Quebec (FRSQ)
- FRQS Clinical Research Scholarship
- Medical Research Council
- European Union
- National Institute for Health Research (NIHR)
- Biomedical Research Centre based at Guy's and St Thomas's NHS Foundation Trust
- King's College London
- National Health and Medical Research Council Senior Research Fellowship [APP1137714]
- University of Queensland Development Fellowship [UQFEL1718945]
- Arthritis Research UK [20000]
- Wellcome Trust [101123, 094134]
- Mrs. Janice Gibson and the Ernest Heine Family Foundation
- Israel Science Foundation [1283/14]
- US NIH NIAMS [1R01AR072199]
- Netherlands Organization for Health Research and Development [ZonMw VIDI 016.136.361]
- NIH/NIAMS [AR063702, AR060981]
- National Institute of Arthritis Musculoskeletal and Skin Diseases [R01 AR041398, R01 AR072199]
- Australian Government Research Training Program Scholarship
- UK NIHR Biomedical Research Centre [201865 2008-12, 2007-12]
- Swedish Research Council
- Swedish Foundation for Strategic Research
- European Calcified Tissue Society
- Torsten and Ragnar Soderberg's Foundation
- Novo Nordisk Foundation
- Knut and Alice Wallenberg Foundation
- NIH [R35 GM119703]
- Wellcome Trust
- Clinical Research Facility
- Medical Research Council Programme [MC_UU_12013/4]
- ALF/LUA research grant from the Sahlgrenska University Hospital
- Lundberg Foundation
- EPSRC [EP/J008192/1] Funding Source: UKRI
- MRC [G0400491, MC_UU_12011/2, MC_U147585819, MC_UU_12013/4, MC_UP_A620_1015, MC_U147585827] Funding Source: UKRI
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 similar to 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 x 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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