1. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects
- Author
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Hans Bisgaard, Leon Eyrich Jessen, John G. Logan, Gudmar Porleifsson, Hou-Feng Zheng, Annelies C. Ham, Tarunveer S. Ahluwalia, Struan F.A. Grant, Yongmei Liu, M. Carola Zillikens, Ivana Nedeljkovic, Mattias Lorentzon, Daniel S. Evans, Kari Stefansson, Jing Hua Zhao, Gunnar Sigurdsson, Fiona E. McGuigan, Rebecca D. Jackson, Douglas P. Kiel, M. Arfan Ikram, David Karasik, J. Brent Richards, Scott Wilson, Tamara B. Harris, Najaf Amin, James F. Wilson, Peter I. Croucher, John A Robbins, Carolina Medina-Gomez, Raimo Joro, Frances M K Williams, Stuart H. Ralston, Unnur Styrkarsdottir, Timo A. Lakka, Jian'an Luan, Cheryl L. Ackert-Bicknell, John P. Walsh, Benjamin H. Mullin, Fernando Pires Hartwig, Bruce M. Psaty, Robert A. Scott, Claes Ohlsson, Janine F. Felix, Bram C. J. van der Eerden, Jonathan H Tobias, Mike A. Nalls, Christian J. Carlsson, Cindy G. Boer, Kun Zhu, Tim D. Spector, Linda Broer, Babette S. Zemel, Martin den Heijer, Mustafa Atalay, Eric S. Orwoll, David M. Evans, Ruifang Li-Gao, John P. Kemp, Katharina E. Schraut, Dennis O. Mook-Kanamori, Kristina Åkesson, Katerina Trajanoska, Maria Nethander, Evangelia E. Ntzani, Cornelia M. van Duijn, Craig E. Pennell, Yanhua Zhou, Ching-Ti Liu, Vincenzo Forgetta, Claudia Langenberg, Fernando Rivadeneira, Vincent W. V. Jaddoe, Nathalie van der Velde, J. H. Duncan Bassett, Bernardo L. Horta, Jeroen van de Peppel, Samuel K. Handelman, Evangelos Evangelou, Klaus Bønnelykke, Renée de Mutsert, Denise H. M. Heppe, Nicholas J. Wareham, Graham R. Williams, Bo L. Chawes, Andre J. van Wijnen, Carol A. Wang, Mohsen Ghanbari, Alessandra Chesi, André G. Uitterlinden, Epidemiology, Erasmus MC other, Internal Medicine, Clinical Genetics, Pediatrics, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Zhao, Jing Hua [0000-0003-4930-3582], Apollo - University of Cambridge Repository, Geriatrics, APH - Aging & Later Life, AMS - Ageing & Morbidty, AMS - Amsterdam Movement Sciences, Wellcome Trust, Pediatric surgery, General practice, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, and IOO
- Subjects
0301 basic medicine ,Aging ,Bone density ,Osteoporosis ,Genome-wide association study ,Bioinformatics ,Medical and Health Sciences ,total-body DXA ,CREB3L1 ,Mice ,0302 clinical medicine ,Bone Density ,GWASs ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Genetics (clinical) ,Bone mineral ,Genetics & Heredity ,Mice, Knockout ,ESR1 ,RANKL ,Age Factors ,11 Medical And Health Sciences ,Single Nucleotide ,Biological Sciences ,Polymorphism, Single Nucleotide/genetics ,genetic correlation ,medicine.anatomical_structure ,Meta-analysis ,Child, Preschool ,Regression Analysis ,musculoskeletal diseases ,Adolescent ,Knockout ,030209 endocrinology & metabolism ,Biology ,Genetic correlation ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Quantitative Trait ,Rare Diseases ,Quantitative Trait, Heritable ,Bone Density/genetics ,Clinical Research ,BMD ,meta-regression ,medicine ,Genetics ,Journal Article ,Animals ,Humans ,Polymorphism ,Preschool ,Heritable ,Genetic association ,Femoral neck ,age-dependent effects ,Human Genome ,Infant, Newborn ,Infant ,06 Biological Sciences ,medicine.disease ,Newborn ,030104 developmental biology ,Good Health and Well Being ,fracture ,Genetic Loci ,Musculoskeletal ,genome-wide association studies ,bone mineral density ,Genome-Wide Association Study - 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.
- Published
- 2018