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. MullinSamuel 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

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)88-102
Number of pages15
JournalAmerican Journal of Human Genetics
Volume102
Issue number1
DOIs
StatePublished - Jan 4 2018

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Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Medina-Gomez, C., Kemp, J. P., Trajanoska, K., Luan, J., Chesi, A., Ahluwalia, T. S., Mook-Kanamori, D. O., Ham, A., Hartwig, F. P., Evans, D. S., Joro, R., Nedeljkovic, I., Zheng, H. F., Zhu, K., Atalay, M., Liu, C. T., Nethander, M., Broer, L., Porleifsson, G., ... 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), 88-102. https://doi.org/10.1016/j.ajhg.2017.12.005