Authors

Carolina Medina-Gómez
John P. Kemp
Katerina Trajanoska
Jian'an Luan
Alessandra Chesi
Tarunveer S. Ahluwalia
Dennis O. Mook-Kanamori
Annelies C. 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, Australian Catholic UniversityFollow
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

Publication Date

2018

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.

School/Institute

Mary MacKillop Institute for Health Research

Document Type

Journal Article

Access Rights

ERA Access

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