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

Medina-Gomez, Carolina; Kemp, John P.; Trajanoska, Katerina; Luan, Jian'an; Chesi, Alessandra; Ahluwalia, Tarunveer S.; Mook-Kanamori, Dennis O.; Ham, Annelies; Hartwig, Fernando P. and Evans, Daniel S., et al. (2018) In American Journal of Human Genetics 102(1). p.88-102
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;... (More)

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.

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age-dependent effects, BMD, bone mineral density, CREB3L1, ESR1, fracture, genetic correlation, genome-wide association studies, GWASs, meta-regression, RANKL, total-body DXA
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American Journal of Human Genetics
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102
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1
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15 pages
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Cell Press
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  • scopus:85039787162
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0002-9297
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English
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yes
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11dd8a80-2867-4fca-9f19-2348b1a5585c
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2018-01-23 14:40:23
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2018-05-29 09:18:59
@article{11dd8a80-2867-4fca-9f19-2348b1a5585c,
  abstract     = {<p>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.</p>},
  author       = {Medina-Gomez, Carolina and Kemp, John P. and Trajanoska, Katerina and Luan, Jian'an and Chesi, Alessandra and Ahluwalia, Tarunveer S. and Mook-Kanamori, Dennis O. and Ham, Annelies and Hartwig, Fernando P. and Evans, Daniel S. and Joro, Raimo and Nedeljkovic, Ivana and Zheng, Hou Feng and Zhu, Kun and Atalay, Mustafa and Liu, Ching Ti and Nethander, Maria and Broer, Linda and Porleifsson, Gudmar and Mullin, Benjamin H. and Handelman, Samuel K. and Nalls, Mike A. and Jessen, Leon E. and Heppe, Denise H.M. and Richards, J. Brent and Wang, Carol and Chawes, Bo and Schraut, Katharina E. and Amin, Najaf and Wareham, Nick and Karasik, David and Van der Velde, Nathalie and Ikram, M. Arfan and Zemel, Babette S. and Zhou, Yanhua and Carlsson, Christian J. and Liu, Yongmei and McGuigan, Fiona E. and Boer, Cindy G. and Bønnelykke, Klaus and Ralston, Stuart H. and Robbins, John A. and Walsh, John P. and Zillikens, M. Carola and Langenberg, Claudia and Li-Gao, Ruifang and Williams, Frances M.K. and Harris, Tamara B. and Akesson, Kristina and Jackson, Rebecca D. and Sigurdsson, Gunnar and den Heijer, Martin and van der Eerden, Bram C.J. and van de Peppel, Jeroen and Spector, Timothy D. and Pennell, Craig and Horta, Bernardo L. and Felix, Janine F. and Zhao, Jing Hua and Wilson, Scott G. and de Mutsert, Renée and Bisgaard, Hans and Styrkársdóttir, Unnur and Jaddoe, Vincent W. and Orwoll, Eric and Lakka, Timo A. and Scott, Robert and Grant, Struan F.A. and Lorentzon, Mattias and van Duijn, Cornelia M. and Wilson, James F. and Stefansson, Kari and Psaty, Bruce M. and Kiel, Douglas P. and Ohlsson, Claes and Ntzani, Evangelia and van Wijnen, Andre J. and Forgetta, Vincenzo and Ghanbari, Mohsen and Logan, John G. and Williams, Graham R. and Bassett, J. H.Duncan and Croucher, Peter I. and Evangelou, Evangelos and Uitterlinden, Andre G. and Ackert-Bicknell, Cheryl L. and Tobias, Jonathan H. and Evans, David M. and Rivadeneira, Fernando},
  issn         = {0002-9297},
  keyword      = {age-dependent effects,BMD,bone mineral density,CREB3L1,ESR1,fracture,genetic correlation,genome-wide association studies,GWASs,meta-regression,RANKL,total-body DXA},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {88--102},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects},
  url          = {http://dx.doi.org/},
  volume       = {102},
  year         = {2018},
}