Journal article
Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects
Erasmus University Rotterdam1
McGill University2
Sir Charles Gairdner Hospital3
Boston University4
University of Gothenburg5
deCODE Genetics6
Wayne State University7
National Institute on Aging8
Department of Bio and Health Informatics, Technical University of Denmark9
National Veterinary Institute, Technical University of Denmark10
Immunoinformatics and Machine Learning, Department of Bio and Health Informatics, Technical University of Denmark11
University of Queensland12
T-cells & Cancer, Division of Immunology & Vaccinology, National Veterinary Institute, Technical University of Denmark13
University of Western Australia14
University of Edinburgh15
Hebrew SeniorLife16
Wake Forest School of Medicine17
Lund University18
University of California at Davis19
King's College London20
Ohio State University21
The National University Hospital of Iceland22
University of Cambridge23
Oregon Health and Science University24
University of Washington25
University of Ioannina26
Mayo Clinic27
Imperial College London28
Garvan Institute of Medical Research29
University of Rochester30
University of Bristol31
The Children's Hospital of Philadelphia32
University of Copenhagen33
Leiden University34
Federal University of Pelotas35
California Pacific Medical Center36
University of Eastern Finland37
...and 27 moreBone 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.
Language: | English |
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Publisher: | Elsevier |
Year: | 2018 |
Pages: | 88-102 |
ISSN: | 15376605 and 00029297 |
Types: | Journal article |
DOI: | 10.1016/j.ajhg.2017.12.005 |
ORCIDs: | 0000-0001-6846-6243 , 0000-0003-4131-7592 and Jessen, Leon Eyrich |
Adolescent Age Factors Animals BMD Bone Density Bone Density/genetics CREB3L1 Child Child, Preschool ESR1 GWASs Genetic Loci Genome-Wide Association Study Humans Infant Infant, Newborn Mice, Knockout Polymorphism, Single Nucleotide Polymorphism, Single Nucleotide/genetics Quantitative Trait, Heritable RANKL Regression Analysis age-dependent effects bone mineral density fracture genetic correlation genome-wide association studies meta-regression total-body DXA