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

Journal article
Authors C. Medina-Gomez
J. P. Kemp
K. Trajanoska
J. Luan
A. Chesi
T. S. Ahluwalia
D. O. Mook-Kanamori
A. Ham
F. P. Hartwig
D. S. Evans
R. Joro
I. Nedeljkovic
H. F. Zheng
K. Zhu
M. Atalay
C. T. Liu
Maria Nethander
L. Broer
G. Porleifsson
B. H. Mullin
S. K. Handelman
M. A. Nalls
L. E. Jessen
D. H. M. Heppe
J. B. Richards
C. Wang
B. Chawes
K. E. Schraut
N. Amin
N. Wareham
D. Karasik
N. Van der Velde
M. A. Ikram
B. S. Zemel
Y. Zhou
C. J. Carlsson
Y. Liu
F. E. McGuigan
C. G. Boer
K. Bønnelykke
S. H. Ralston
J. A. Robbins
J. P. Walsh
M. C. Zillikens
C. Langenberg
R. Li-Gao
F. M. K. Williams
T. B. Harris
K. Akesson
R. D. Jackson
G. Sigurdsson
M. den Heijer
B. C. J. van der Eerden
J. van de Peppel
T. D. Spector
C. Pennell
B. L. Horta
J. F. Felix
J. H. Zhao
S. G. Wilson
R. de Mutsert
H. Bisgaard
U. Styrkársdóttir
V. W. Jaddoe
E. Orwoll
T. A. Lakka
R. Scott
S. F. A. Grant
Mattias Lorentzon
C. M. van Duijn
J. F. Wilson
K. Stefansson
B. M. Psaty
D. P. Kiel
Claes Ohlsson
E. Ntzani
A. J. van Wijnen
V. Forgetta
M. Ghanbari
J. G. Logan
G. R. Williams
J. H. D. Bassett
P. I. Croucher
E. Evangelou
A. G. Uitterlinden
C. L. Ackert-Bicknell
J. H. Tobias
D. M. Evans
F. Rivadeneira
Published in American Journal of Human Genetics
Volume 102
Issue 1
Pages 88-102
ISSN 00029297 (ISSN)
Publication year 2018
Published at Core Facilities, Bioinformatics
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 88-102
Language en
Links https://doi.org/10.1016/j.ajhg.2017...
Keywords age-dependent effects, BMD, bone mineral density, CREB3L1, ESR1, fracture, genetic correlation, genome-wide association studies, GWASs, meta-regression, RANKL, total-body DXA
Subject categories Clinical Medicine

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

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