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

Medina-Gomez, C. and Kemp, J. P. and Trajanoska, K. and Luan, J. and Chesi, A. and Ahluwalia, T. S. and Mook-Kanamori, D. O. and Ham, A. and Hartwig, F. P. and Evans, D. S. and Joro, R. and Nedeljkovic, I. and Zheng, H. F. and Zhu, K. and Atalay, M. and Liu, C. T. and Nethander, M. and Broer, L. and Porleifsson, G. and Mullin, B. H. and Handelman, S. K. and Nalls, M. A. and Jessen, L. E. and Heppe, D. H. M. and Richards, J. B. and Wang, C. and Chawes, B. and Schraut, K. E. and Amin, N. and Wareham, N. and Karasik, D. and Van der Velde, N. and Ikram, M. A. and Zemel, B. S. and Zhou, Y. and Carlsson, C. J. and Liu, Y. and McGuigan, F. E. and Boer, C. G. and Bønnelykke, K. and Ralston, S. H. and Robbins, J. A. and Walsh, J. P. and Zillikens, M. C. and Langenberg, C. and Li-Gao, R. and Williams, F. M. K. and Harris, T. B. and Akesson, K. and Jackson, R. D. and Sigurdsson, G. and den Heijer, M. and van der Eerden, B. C. J. and van de Peppel, J. and Spector, T. D. and Pennell, C. and Horta, B. L. and Felix, J. F. and Zhao, J. H. and Wilson, S. G. and de Mutsert, R. and Bisgaard, H. and Styrkársdóttir, U. and Jaddoe, V. W. and Orwoll, E. and Lakka, T. A. and Scott, R. and Grant, S. F. A. and Lorentzon, M. and van Duijn, C. M. and Wilson, J. F. and Stefansson, K. and Psaty, B. M. and Kiel, D. P. and Ohlsson, C. and Ntzani, E. and van Wijnen, A. J. and Forgetta, V. and Ghanbari, M. and Logan, J. G. and Williams, G. R. and Bassett, J. H. D. and Croucher, P. I. and Evangelou, E. and Uitterlinden, A. G. and Ackert-Bicknell, C. L. and Tobias, J. H. and Evans, D. M. and Rivadeneira, F. (2018) Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects. American Journal of Human Genetics, 102 (1). pp. 88-102.

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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. © 2017 American Society of Human Genetics

Item Type: Article
Additional Information: Cited By :34 Export Date: 16 February 2020 CODEN: AJHGA Correspondence Address: Rivadeneira, F.; Department of Epidemiology, Erasmus MCNetherlands; email: f.rivadeneira@erasmusmc.nl
Uncontrolled Keywords: age-dependent effects BMD bone mineral density CREB3L1 ESR1 fracture genetic correlation genome-wide association studies GWASs meta-regression RANKL total-body DXA estrogen receptor alpha osteoclast differentiation factor Smad protein age Article bone density cell growth dual energy X ray absorptiometry enhancer region gene cluster gene function gene linkage disequilibrium gene locus gene overexpression genetic trait genetic variation genome-wide association study heritability human musculoskeletal system nonhuman osteoporosis priority journal promoter region risk assessment single nucleotide polymorphism systematic review adolescent animal child genetics infant knockout mouse meta analysis newborn preschool child quantitative trait regression analysis Age Factors Animals Child, Preschool Genetic Loci Humans Infant, Newborn Mice, Knockout Polymorphism, Single Nucleotide Quantitative Trait, Heritable
Subjects: WE Musculoskeletal system
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 09 May 2020 07:33
Last Modified: 09 May 2020 07:33
URI: http://eprints.mums.ac.ir/id/eprint/17396

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