An Atlas of Human and Murine Genetic Influences on Osteoporosis
An Atlas of Human and Murine Genetic Influences on Osteoporosis
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 developed “STARLinG”, a method to identify Target Genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites. STARLinG identified Target Genes 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, indicating impaired bone quality. 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.
Croucher Peter I.、Goltzman David、Reeve Jonathan、Grundberg Elin、Adams David J.、Lelliott Christopher J.、Hinds David A.、Williams Graham R.、Youlten Scott E.、Logan John G.、Forgetta Vincenzo、Mohanty Sindhu、Vijay Jinchu、Simon Marie-Michelle、Leitch Victoria D.、Sparkes Penny C.、Baldock Paul、Vaillancourt Suzanne M.、Kaptoge Stephen、Ntzani Evangelia、Ackert-Bicknell Cheryl L.、Kiel Douglas P.、Tobias Jonathan H.、Morris John A.、Pollard Andrea S.、Evans David M.、Evangelou Evangelos、Komla-Ebri Davide、Hassell Thomas、Maurano Matthew T.、Quinn Julian、Kemp John P.、Luco Aimee Lee、Dewhurst Hannah F.、Vulpescu Nicholas A.、Karasik David、Rivadeneira Fernando、Medina-Gomez Carolina、Cooper Cyrus、Sergio C. Marcelo、Mannan Naila S.、Harvey Nicholas C.、Adoum Anne-Tounsia、Ghirardello Elena J.、Kleinman Aaron、Bassett J.H. Duncan、Ohlsson Claes、Hsu Yi-Hsiang、Chai Ryan、Trajanoska Katerina、Pramatarova Albena、Gregson Celia L.、Nguyen-Yamamoto Loan、Laurent Laetitia、Richards J. Brent、Curry Katharine F.、Beltejar Michael-John G、Butterfield Natalie C.、Adams Douglas J
Garvan Institute of Medical ResearchResearch Institute of the McGill University Health CentreNIHR Musculoskeletal Biomedical Research Unit, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesMcGill University and Genome Quebec Innovation Centre||Children?ˉs Mercy Hospitals and Clinics, Kansas CityWellcome Trust Sanger Institute, Wellcome Genome CampusWellcome Trust Sanger Institute, Wellcome Genome CampusDepartment of ResearchMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonGarvan Institute of Medical ResearchMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonLady Davis Institute, Jewish General Hospital, McGill UniversityGarvan Institute of Medical ResearchMcGill University and Genome Quebec Innovation CentreMcGill University and Genome Quebec Innovation CentreMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonGarvan Institute of Medical ResearchDepartments of Medicine and Epidemiology, Biostatistics & Occupational Health, McGill UniversityDepartment of Public Health and Primary Care, University of CambridgeDepartment of Hygiene and Epidemiology, University of Ioannina Medical SchoolCenter for Musculoskeletal Research, Department of Orthopaedics, University of RochesterInstitute for Aging Research, Hebrew SeniorLifeMusculoskeletal Research Unit, Department of Translational Health Sciences, University of BristolDepartment of Human Genetics, McGill University||Lady Davis Institute, Jewish General Hospital, McGill UniversityMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonUniversity of Queensland Diamantina Institute, Translational Research Institute||MRC Integrative Epidemiology Unit, University of BristolDepartment of Hygiene and Epidemiology, University of Ioannina Medical SchoolMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonUniversity of Queensland Diamantina Institute, Translational Research InstituteInstitute for Systems Genetics, New York University Langone Medical CenterGarvan Institute of Medical ResearchUniversity of Queensland Diamantina Institute, Translational Research Institute||MRC Integrative Epidemiology Unit, University of BristolResearch Institute of the McGill University Health CentreMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonInstitute for Systems Genetics, New York University Langone Medical CenterInstitute for Aging Research, Hebrew SeniorLifeDepartment of Internal Medicine, Erasmus Medical CenterDepartment of Internal Medicine, Erasmus Medical CenterMRC Lifecourse Epidemiology Unit, University of Southampton||NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust||NIHR Oxford Biomedical Research Centre, University of OxfordGarvan Institute of Medical ResearchMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonMRC Lifecourse Epidemiology Unit, University of Southampton||NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation TrustMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonDepartment of ResearchMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonDepartment of Internal Medicine and Clinical Nutrition, University of GothenburgInstitute for Aging Research, Hebrew SeniorLifeGarvan Institute of Medical ResearchDepartment of Internal Medicine, Erasmus Medical CenterMcGill University and Genome Quebec Innovation CentreMusculoskeletal Research Unit, Department of Translational Health Sciences, University of BristolResearch Institute of the McGill University Health CentreLady Davis Institute, Jewish General Hospital, McGill UniversityDepartment of Human Genetics, McGill University||Lady Davis Institute, Jewish General Hospital, McGill University||Departments of Medicine and Epidemiology, Biostatistics & Occupational Health, McGill University||Department of Twin Research and Genetic Epidemiology, King?ˉs College LondonMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonDepartment of Biomedical Genetics, University of RochesterMolecular Endocrinology Laboratory, Department of Medicine, Imperial College LondonDepartment of Orthopedics, University of Colorado Anschutz Medical Campus
基础医学遗传学生理学
Croucher Peter I.,Goltzman David,Reeve Jonathan,Grundberg Elin,Adams David J.,Lelliott Christopher J.,Hinds David A.,Williams Graham R.,Youlten Scott E.,Logan John G.,Forgetta Vincenzo,Mohanty Sindhu,Vijay Jinchu,Simon Marie-Michelle,Leitch Victoria D.,Sparkes Penny C.,Baldock Paul,Vaillancourt Suzanne M.,Kaptoge Stephen,Ntzani Evangelia,Ackert-Bicknell Cheryl L.,Kiel Douglas P.,Tobias Jonathan H.,Morris John A.,Pollard Andrea S.,Evans David M.,Evangelou Evangelos,Komla-Ebri Davide,Hassell Thomas,Maurano Matthew T.,Quinn Julian,Kemp John P.,Luco Aimee Lee,Dewhurst Hannah F.,Vulpescu Nicholas A.,Karasik David,Rivadeneira Fernando,Medina-Gomez Carolina,Cooper Cyrus,Sergio C. Marcelo,Mannan Naila S.,Harvey Nicholas C.,Adoum Anne-Tounsia,Ghirardello Elena J.,Kleinman Aaron,Bassett J.H. Duncan,Ohlsson Claes,Hsu Yi-Hsiang,Chai Ryan,Trajanoska Katerina,Pramatarova Albena,Gregson Celia L.,Nguyen-Yamamoto Loan,Laurent Laetitia,Richards J. Brent,Curry Katharine F.,Beltejar Michael-John G,Butterfield Natalie C.,Adams Douglas J.An Atlas of Human and Murine Genetic Influences on Osteoporosis[EB/OL].(2025-03-28)[2025-05-29].https://www.biorxiv.org/content/10.1101/338863.点此复制
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