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

Autor: Morris JA; Department of Human Genetics, McGill University, Montréal, Québec, Canada.; Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada., Kemp JP; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK., Youlten SE; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Laurent L; Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada., Logan JG; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Chai RC; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Vulpescu NA; Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA., Forgetta V; Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada., Kleinman A; Department of Research, 23andMe, Inc., Mountain View, CA, USA., Mohanty ST; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Sergio CM; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Quinn J; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Nguyen-Yamamoto L; Research Institute of the McGill University Health Centre, Montréal, Québec, Canada., Luco AL; Research Institute of the McGill University Health Centre, Montréal, Québec, Canada., Vijay J; McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada., Simon MM; McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada., Pramatarova A; McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada., Medina-Gomez C; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands., Trajanoska K; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands., Ghirardello EJ; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Butterfield NC; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Curry KF; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Leitch VD; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Sparkes PC; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Adoum AT; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Mannan NS; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Komla-Ebri DSK; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Pollard AS; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Dewhurst HF; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Hassall TAD; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia., Beltejar MG; Department of Biomedical Genetics, University of Rochester, Rochester, NY, USA., Adams DJ; Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Vaillancourt SM; Department of Medicine, McGill University, Montréal, Québec, Canada., Kaptoge S; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Baldock P; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Cooper C; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK., Reeve J; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK., Ntzani EE; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.; Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, RI, USA., Evangelou E; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.; Department of Epidemiology and Biostatistics, Imperial College London, London, UK., Ohlsson C; Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden., Karasik D; Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA., Rivadeneira F; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands., Kiel DP; Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA., Tobias JH; Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK., Gregson CL; Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK., Harvey NC; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK., Grundberg E; McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada.; Children's Mercy Hospitals and Clinics, Kansas City, MO, USA., Goltzman D; Research Institute of the McGill University Health Centre, Montréal, Québec, Canada., Adams DJ; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Lelliott CJ; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Hinds DA; Department of Research, 23andMe, Inc., Mountain View, CA, USA., Ackert-Bicknell CL; Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY, USA., Hsu YH; Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA., Maurano MT; Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA., Croucher PI; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Williams GR; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Bassett JHD; Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK., Evans DM; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. d.evans1@uq.edu.au.; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.evans1@uq.edu.au., Richards JB; Department of Human Genetics, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.; Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.; Department of Medicine, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.; Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. brent.richards@mcgill.ca.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2019 Feb; Vol. 51 (2), pp. 258-266. Date of Electronic Publication: 2018 Dec 31.
DOI: 10.1038/s41588-018-0302-x
Abstrakt: 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.
Databáze: MEDLINE