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

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dc.contributor.authorMedina-Gomez, Carolina
dc.contributor.authorKemp, John P
dc.contributor.authorTrajanoska, Katerina
dc.contributor.authorLuan, Jian'an
dc.contributor.authorChesi, Alessandra
dc.contributor.authorAhluwalia, Tarunveer S
dc.contributor.authorMook-Kanamori, Dennis O
dc.contributor.authorHam, Annelies
dc.contributor.authorHartwig, Fernando P
dc.contributor.authorEvans, Daniel S
dc.contributor.authorJoro, Raimo
dc.contributor.authorNedeljkovic, Ivana
dc.contributor.authorZheng, Hou-Feng
dc.contributor.authorZhu, Kun
dc.contributor.authorAtalay, Mustafa
dc.contributor.authorLiu, Ching-Ti
dc.contributor.authorNethander, Maria
dc.contributor.authorBroer, Linda
dc.contributor.authorPorleifsson, Gudmar
dc.contributor.authorMullin, Benjamin H
dc.contributor.authorHandelman, Samuel K
dc.contributor.authorNalls, Mike A
dc.contributor.authorJessen, Leon E
dc.contributor.authorHeppe, Denise HM
dc.contributor.authorRichards, J Brent
dc.contributor.authorWang, Carol
dc.contributor.authorChawes, Bo
dc.contributor.authorSchraut, Katharina E
dc.contributor.authorAmin, Najaf
dc.contributor.authorWareham, Nick
dc.contributor.authorKarasik, David
dc.contributor.authorVan der Velde, Nathalie
dc.contributor.authorIkram, M Arfan
dc.contributor.authorZemel, Babette S
dc.contributor.authorZhou, Yanhua
dc.contributor.authorCarlsson, Christian J
dc.contributor.authorLiu, Yongmei
dc.contributor.authorMcGuigan, Fiona E
dc.contributor.authorBoer, Cindy G
dc.contributor.authorBønnelykke, Klaus
dc.contributor.authorRalston, Stuart H
dc.contributor.authorRobbins, John A
dc.contributor.authorWalsh, John P
dc.contributor.authorZillikens, M Carola
dc.contributor.authorLangenberg, Claudia
dc.contributor.authorLi-Gao, Ruifang
dc.contributor.authorWilliams, Frances MK
dc.contributor.authorHarris, Tamara B
dc.contributor.authorAkesson, Kristina
dc.contributor.authorJackson, Rebecca D
dc.contributor.authorSigurdsson, Gunnar
dc.contributor.authorden Heijer, Martin
dc.contributor.authorvan der Eerden, Bram CJ
dc.contributor.authorvan de Peppel, Jeroen
dc.contributor.authorSpector, Timothy D
dc.contributor.authorPennell, Craig
dc.contributor.authorHorta, Bernardo L
dc.contributor.authorFelix, Janine F
dc.contributor.authorZhao, Jing Hua
dc.contributor.authorWilson, Scott G
dc.contributor.authorde Mutsert, Renée
dc.contributor.authorBisgaard, Hans
dc.contributor.authorStyrkársdóttir, Unnur
dc.contributor.authorJaddoe, Vincent W
dc.contributor.authorOrwoll, Eric
dc.contributor.authorLakka, Timo A
dc.contributor.authorScott, Robert
dc.contributor.authorGrant, Struan FA
dc.contributor.authorLorentzon, Mattias
dc.contributor.authorvan Duijn, Cornelia M
dc.contributor.authorWilson, James F
dc.contributor.authorStefansson, Kari
dc.contributor.authorPsaty, Bruce M
dc.contributor.authorKiel, Douglas P
dc.contributor.authorOhlsson, Claes
dc.contributor.authorNtzani, Evangelia
dc.contributor.authorvan Wijnen, Andre J
dc.contributor.authorForgetta, Vincenzo
dc.contributor.authorGhanbari, Mohsen
dc.contributor.authorLogan, John G
dc.contributor.authorWilliams, Graham R
dc.contributor.authorBassett, JH Duncan
dc.contributor.authorCroucher, Peter I
dc.contributor.authorEvangelou, Evangelos
dc.contributor.authorUitterlinden, Andre G
dc.contributor.authorAckert-Bicknell, Cheryl L
dc.contributor.authorTobias, Jonathan H
dc.contributor.authorEvans, David M
dc.contributor.authorRivadeneira, Fernando
dc.contributor.orcidLuan, Jian'an [0000-0003-3137-6337]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.contributor.orcidZhao, Jing Hua [0000-0003-4930-3582]
dc.date.accessioned2018-03-14T15:55:31Z
dc.date.available2018-03-14T15:55:31Z
dc.date.issued2018-01-04
dc.description.abstractBone 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.
dc.format.mediumPrint
dc.identifier.doi10.17863/CAM.21080
dc.identifier.eissn1537-6605
dc.identifier.issn0002-9297
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/274004
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.ajhg.2017.12.005
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectBMD
dc.subjectCREB3L1
dc.subjectESR1
dc.subjectGWASs
dc.subjectRANKL
dc.subjectage-dependent effects
dc.subjectbone mineral density
dc.subjectfracture
dc.subjectgenetic correlation
dc.subjectgenome-wide association studies
dc.subjectmeta-regression
dc.subjecttotal-body DXA
dc.subjectAdolescent
dc.subjectAge Factors
dc.subjectAnimals
dc.subjectBone Density
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectGenetic Loci
dc.subjectGenome-Wide Association Study
dc.subjectHumans
dc.subjectInfant
dc.subjectInfant, Newborn
dc.subjectMice, Knockout
dc.subjectPolymorphism, Single Nucleotide
dc.subjectQuantitative Trait, Heritable
dc.subjectRegression Analysis
dc.titleLife-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.
dc.typeArticle
dcterms.dateAccepted2017-11-30
prism.endingPage102
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameAm J Hum Genet
prism.startingPage88
prism.volume102
pubs.funder-project-idMedical Research Council (MC_UU_12015/1)
pubs.funder-project-idMRC (MC_PC_13048)
pubs.funder-project-idMRC (MC_PC_13046)
pubs.funder-project-idMedical Research Council (MR/N003284/1)
pubs.funder-project-idMedical Research Council (G0401527)
pubs.funder-project-idMedical Research Council (G1000143)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
pubs.funder-project-idTCC (None)
pubs.funder-project-idMedical Research Council (G0401527/1)
rioxxterms.licenseref.startdate2018-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1016/j.ajhg.2017.12.005

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