Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Carolina Medina-Gomez; John P Kemp; Katerina Trajanoska; Jian'an Luan; Alessandra Chesi; Tarunveer S Ahluwalia; Dennis O Mook-Kanamori; Annelies Ham; Fernando P Hartwig; Daniel S Evans; Raimo Joro; Ivana Nedeljkovic; Hou-Feng Zheng; Kun Zhu; Mustafa Atalay; Ching-Ti Liu; Maria Nethander; Linda Broer; Gudmar Porleifsson; Benjamin H Mullin; Samuel K Handelman; Mike A Nalls; Leon E Jessen; Denise H M Heppe; J Brent Richards; Carol Wang; Bo Chawes; Katharina E Schraut; Najaf Amin; Nick Wareham; David Karasik; Nathalie Van der Velde; M Arfan Ikram; Babette S Zemel; Yanhua Zhou; Christian J Carlsson; Yongmei Liu; Fiona E McGuigan; Cindy G Boer; Klaus Bønnelykke; Stuart H Ralston; John A Robbins; John P Walsh; M Carola Zillikens; Claudia Langenberg; Ruifang Li-Gao; Frances M K Williams; Tamara B Harris; Kristina Akesson; Rebecca D Jackson; Gunnar Sigurdsson; Martin den Heijer; Bram C J van der Eerden; Jeroen van de Peppel; Timothy D Spector; Craig Pennell; Bernardo L Horta; Janine F Felix; Jing Hua Zhao; Scott G Wilson; Renée de Mutsert; Hans Bisgaard; Unnur Styrkársdóttir; Vincent W Jaddoe; Eric Orwoll; Timo A Lakka; Robert Scott; Struan F A Grant; Mattias Lorentzon; Cornelia M van Duijn; James F Wilson; Kari Stefansson; Bruce M Psaty; Douglas P Kiel; Claes Ohlsson; Evangelia Ntzani; Andre J van Wijnen; Vincenzo Forgetta; Mohsen Ghanbari; John G Logan; Graham R Williams; J H Duncan Bassett; Peter I Croucher; Evangelos Evangelou; Andre G Uitterlinden; Cheryl L Ackert-Bicknell; Jonathan H Tobias; David M Evans; Fernando Rivadeneira

doi:10.1016/j.ajhg.2017.12.005

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Am J Hum Genet. 2018 Jan 4;102(1):88-102. doi: 10.1016/j.ajhg.2017.12.005.

Authors

Carolina Medina-Gomez¹, John P Kemp², Katerina Trajanoska³, Jian'an Luan⁴, Alessandra Chesi⁵, Tarunveer S Ahluwalia⁶, Dennis O Mook-Kanamori⁷, Annelies Ham⁸, Fernando P Hartwig⁹, Daniel S Evans¹⁰, Raimo Joro¹¹, Ivana Nedeljkovic¹², Hou-Feng Zheng¹³, Kun Zhu¹⁴, Mustafa Atalay¹¹, Ching-Ti Liu¹⁵, Maria Nethander¹⁶, Linda Broer⁸, Gudmar Porleifsson¹⁷, Benjamin H Mullin¹⁴, Samuel K Handelman¹⁸, Mike A Nalls¹⁹, Leon E Jessen²⁰, Denise H M Heppe²¹, J Brent Richards²², Carol Wang²³, Bo Chawes²⁰, Katharina E Schraut²⁴, Najaf Amin¹², Nick Wareham⁴, David Karasik²⁵, Nathalie Van der Velde²⁶, M Arfan Ikram¹², Babette S Zemel²⁷, Yanhua Zhou¹⁵, Christian J Carlsson²⁰, Yongmei Liu²⁸, Fiona E McGuigan²⁹, Cindy G Boer⁸, Klaus Bønnelykke²⁰, Stuart H Ralston³⁰, John A Robbins³¹, John P Walsh¹⁴, M Carola Zillikens⁸, Claudia Langenberg⁴, Ruifang Li-Gao³², Frances M K Williams³³, Tamara B Harris³⁴, Kristina Akesson³⁵, Rebecca D Jackson³⁶, Gunnar Sigurdsson³⁷, Martin den Heijer³⁸, Bram C J van der Eerden⁸, Jeroen van de Peppel⁸, Timothy D Spector³³, Craig Pennell²³, Bernardo L Horta⁹, Janine F Felix³⁹, Jing Hua Zhao⁴, Scott G Wilson⁴⁰, Renée de Mutsert³², Hans Bisgaard²⁰, Unnur Styrkársdóttir¹⁷, Vincent W Jaddoe³⁹, Eric Orwoll⁴¹, Timo A Lakka⁴², Robert Scott⁴, Struan F A Grant⁴³, Mattias Lorentzon⁴⁴, Cornelia M van Duijn¹², James F Wilson⁴⁵, Kari Stefansson⁴⁶, Bruce M Psaty⁴⁷, Douglas P Kiel⁴⁸, Claes Ohlsson⁴⁹, Evangelia Ntzani⁵⁰, Andre J van Wijnen⁵¹, Vincenzo Forgetta²², Mohsen Ghanbari⁵², John G Logan⁵³, Graham R Williams⁵³, J H Duncan Bassett⁵³, Peter I Croucher⁵⁴, Evangelos Evangelou⁵⁵, Andre G Uitterlinden¹, Cheryl L Ackert-Bicknell⁵⁶, Jonathan H Tobias⁵⁷, David M Evans², Fernando Rivadeneira⁵⁸

Affiliations

¹ Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
² University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
³ Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
⁴ MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
⁵ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁶ COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen 2820, Denmark; Steno Diabetes Center, Copenhagen 2820, Denmark.
⁷ Department of Clinical Epidemiology, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands.
⁸ Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
⁹ Postgraduate Program in Epidemiology, Federal University of Pelotas, 96020220 Pelotas, Brazil.
¹⁰ California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
¹¹ Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio 70211, Finland.
¹² Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
¹³ Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, QC H3A 1A2, Canada; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou, 100080 Zhejiang, China; Institute of Aging Research and the Affiliated Hospital, School of Medicine, Hangzhou Normal University, Hangzhou, 311121 Zhejiang, China.
¹⁴ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Crawley, WA 6009, Australia.
¹⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02131, USA.
¹⁶ Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden.
¹⁷ deCODE Genetics/Amgen, Reykjavik 101, Iceland.
¹⁸ Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.
¹⁹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD 20812, USA.
²⁰ COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen 2820, Denmark.
²¹ The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
²² Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, QC H3A 1A2, Canada; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
²³ School of Women's and Infants' Health, University of Western Australia, Crawley, WA 6009, Australia.
²⁴ Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH16 4UX, Scotland; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland.
²⁵ Hebrew SeniorLife, Institute for Aging Research, Roslindale, MA 02131, USA; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel.
²⁶ Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Internal Medicine, Section of Geriatrics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
²⁷ Division of GI, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²⁸ Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
²⁹ Lund University, Department of Clinical Sciences Malmö, Clinical and Molecular Osteoporosis Research Unit, 20502 Malmö, Sweden.
³⁰ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland.
³¹ Department of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
³² Department of Clinical Epidemiology, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands.
³³ Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
³⁴ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
³⁵ Lund University, Department of Clinical Sciences Malmö, Clinical and Molecular Osteoporosis Research Unit, 20502 Malmö, Sweden; Skåne University Hospital, Department of Orthopedics, 21428 Malmö, Sweden.
³⁶ Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
³⁷ Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, Reykjavik 101, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
³⁸ Department of Clinical Epidemiology, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands; Department of Clinical Epidemiology and Department of Internal Medicine, VU Medical Center, 1081 HV Amsterdam, the Netherlands.
³⁹ The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Pediatrics, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
⁴⁰ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Crawley, WA 6009, Australia; Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
⁴¹ Department of Public Health & Preventive Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
⁴² Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio 70211, Finland; Kuopio Research Institute of Exercise Medicine, Kuopio 70100, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio 70210, Finland.
⁴³ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴⁴ Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, 40530 Gothenburg, Sweden.
⁴⁵ Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH16 4UX, Scotland; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland.
⁴⁶ deCODE Genetics/Amgen, Reykjavik 101, Iceland; Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, Reykjavik 101, Iceland.
⁴⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
⁴⁸ Hebrew SeniorLife, Institute for Aging Research, Roslindale, MA 02131, USA; Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Boston, MA 02115, USA.
⁴⁹ Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden.
⁵⁰ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece.
⁵¹ Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
⁵² Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁵³ Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London W12 0NN, UK.
⁵⁴ Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁵⁵ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK.
⁵⁶ Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642,USA.
⁵⁷ School of Clinical Sciences, University of Bristol, Bristol BS10 5NB, UK.
⁵⁸ Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands. Electronic address: f.rivadeneira@erasmusmc.nl.

Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Keywords: BMD; CREB3L1; ESR1; GWASs; RANKL; age-dependent effects; bone mineral density; fracture; genetic correlation; genome-wide association studies; meta-regression; total-body DXA.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Age Factors
Animals
Bone Density / genetics*
Child
Child, Preschool
Genetic Loci
Genome-Wide Association Study*
Humans
Infant
Infant, Newborn
Mice, Knockout
Polymorphism, Single Nucleotide / genetics
Quantitative Trait, Heritable
Regression Analysis

Abstract

Publication types

MeSH terms

Grants and funding