1. An atlas of genetic influences on osteoporosis in humans and mice
- Author
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Morris, JA, Kemp, JP, Youlten, SE, Laurent, L, Logan, JG, Chai, RC, Vulpescu, NA, Forgetta, V, Kleinman, A, Mohanty, ST, Sergio, CM, Quinn, J, Nguyen-Yamamoto, L, Luco, A-L, Vijay, J, Simon, M-M, Pramatarova, A, Medina-Gomez, C, Trajanoska, K, Ghirardello, EJ, Butterfield, NC, Curry, KF, Leitch, VD, Sparkes, PC, Adoum, A-T, Mannan, NS, Komla-Ebri, DSK, Pollard, AS, Dewhurst, HF, Hassall, TAD, Beltejar, M-JG, Agee, M, Alipanahi, B, Auton, A, Bell, RK, Bryc, K, Elson, SL, Fontanillas, P, Furlotte, NA, McCreight, JC, Huber, KE, Litterman, NK, McIntyre, MH, Mountain, JL, Noblin, ES, Northover, CAM, Pitts, SJ, Sathirapongsasuti, JF, Sazonova, OV, Shelton, JF, Shringarpure, S, Tian, C, Tung, JY, Vacic, V, Wilson, CH, Adams, DJ, Vaillancourt, SM, Kaptoge, S, Baldock, P, Cooper, C, Reeve, J, Ntzani, EE, Evangelou, E, Ohlsson, C, Karasik, D, Rivadeneira, F, Kiel, DP, Tobias, JH, Gregson, CL, Harvey, NC, Grundberg, E, Goltzman, D, Lelliott, CJ, Hinds, DA, Ackert-Bicknell, CL, Hsu, Y-H, Maurano, MT, Croucher, PI, Williams, GR, Bassett, JHD, Evans, DM, Richards, JB, Wellcome Trust, and Internal Medicine
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CHROMATIN ,Male ,Bone density ,Osteoporosis ,Genome-wide association study ,Fractures, Bone ,Mice ,0302 clinical medicine ,Bone Density ,CALCANEUS ,11 Medical and Health Sciences ,Bone mineral ,Genetics & Heredity ,Mice, Knockout ,0303 health sciences ,HERITABILITY ,Middle Aged ,Phenotype ,3. Good health ,Female ,BONE-MINERAL DENSITY ,Life Sciences & Biomedicine ,Adult ,medicine.medical_specialty ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,23andMe Research Team ,Article ,03 medical and health sciences ,FRACTURES ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,HEEL ,030304 developmental biology ,Aged ,Science & Technology ,HIP ,Bone fracture ,Odds ratio ,06 Biological Sciences ,medicine.disease ,Endocrinology ,QUANTITATIVE ULTRASOUND ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Developmental Biology - 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.
- Published
- 2018
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