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

Carolina Medina-Gomez, John P. Kemp, Katerina Trajanoska, Jian'an Luan, Alessandra Chesi, Tarunveer S. Ahluwalia, Dennis O. Mook-Kanamori, Annelies 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 & 69 others 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, 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

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)88-102
Number of pages15
JournalAmerican Journal of Human Genetics
Volume102
Issue number1
DOIs
Publication statusPublished - 4 Jan 2018

Fingerprint

Genome-Wide Association Study
Bone Density
Meta-Analysis
Osteoporosis
Bone and Bones
Musculoskeletal System
Femur Neck
Genetic Promoter Regions
Cluster Analysis
Spine
Age Groups
Health
Growth

Cite this

Medina-Gomez, C., Kemp, J. P., Trajanoska, K., Luan, J., Chesi, A., Ahluwalia, T. S., ... Rivadeneira, F. (2018). Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects. American Journal of Human Genetics, 102(1), 88-102. https://doi.org/10.1016/j.ajhg.2017.12.005
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. ; Evans, Daniel S. ; Joro, Raimo ; Nedeljkovic, Ivana ; Zheng, Hou Feng ; Zhu, Kun ; Atalay, Mustafa ; Liu, Ching Ti ; Nethander, Maria ; Broer, Linda ; Porleifsson, Gudmar ; Mullin, Benjamin H. ; Handelman, Samuel K. ; Nalls, Mike A. ; Jessen, Leon E. ; Heppe, Denise H.M. ; Richards, J. Brent ; Wang, Carol ; Chawes, Bo ; Schraut, Katharina E. ; Amin, Najaf ; Wareham, Nick ; Karasik, David ; Van der Velde, Nathalie ; Ikram, M. Arfan ; Zemel, Babette S. ; Zhou, Yanhua ; Carlsson, Christian J. ; Liu, Yongmei ; McGuigan, Fiona E. ; Boer, Cindy G. ; Bønnelykke, Klaus ; Ralston, Stuart H. ; Robbins, John A. ; Walsh, John P. ; Zillikens, M. Carola ; Langenberg, Claudia ; Li-Gao, Ruifang ; Williams, Frances M.K. ; Harris, Tamara B. ; Akesson, Kristina ; Jackson, Rebecca D. ; Sigurdsson, Gunnar ; den Heijer, Martin ; van der Eerden, Bram C.J. ; van de Peppel, Jeroen ; Spector, Timothy D. ; Pennell, Craig ; Horta, Bernardo L. ; Felix, Janine F. ; Zhao, Jing Hua ; Wilson, Scott G. ; de Mutsert, Renée ; Bisgaard, Hans ; Styrkársdóttir, Unnur ; Jaddoe, Vincent W. ; Orwoll, Eric ; Lakka, Timo A. ; Scott, Robert ; Grant, Struan F.A. ; Lorentzon, Mattias ; van Duijn, Cornelia M. ; Wilson, James F. ; Stefansson, Kari ; Psaty, Bruce M. ; Kiel, Douglas P. ; Ohlsson, Claes ; Ntzani, Evangelia ; van Wijnen, Andre J. ; Forgetta, Vincenzo ; Ghanbari, Mohsen ; Logan, John G. ; Williams, Graham R. ; Bassett, J. H.Duncan ; Croucher, Peter I. ; Evangelou, Evangelos ; Uitterlinden, Andre G. ; Ackert-Bicknell, Cheryl L. ; Tobias, Jonathan H. ; Evans, David M. ; Rivadeneira, Fernando. / Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 1. pp. 88-102.
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Medina-Gomez, C, Kemp, JP, Trajanoska, K, Luan, J, Chesi, A, Ahluwalia, TS, Mook-Kanamori, DO, Ham, A, Hartwig, FP, Evans, DS, Joro, R, Nedeljkovic, I, Zheng, HF, Zhu, K, Atalay, M, Liu, CT, Nethander, M, Broer, L, Porleifsson, G, Mullin, BH, Handelman, SK, Nalls, MA, Jessen, LE, Heppe, DHM, Richards, JB, Wang, C, Chawes, B, Schraut, KE, Amin, N, Wareham, N, Karasik, D, Van der Velde, N, Ikram, MA, Zemel, BS, Zhou, Y, Carlsson, CJ, Liu, Y, McGuigan, FE, Boer, CG, Bønnelykke, K, Ralston, SH, Robbins, JA, Walsh, JP, Zillikens, MC, Langenberg, C, Li-Gao, R, Williams, FMK, Harris, TB, Akesson, K, Jackson, RD, Sigurdsson, G, den Heijer, M, van der Eerden, BCJ, van de Peppel, J, Spector, TD, Pennell, C, Horta, BL, Felix, JF, Zhao, JH, Wilson, SG, de Mutsert, R, Bisgaard, H, Styrkársdóttir, U, Jaddoe, VW, Orwoll, E, Lakka, TA, Scott, R, Grant, SFA, Lorentzon, M, van Duijn, CM, Wilson, JF, Stefansson, K, Psaty, BM, Kiel, DP, Ohlsson, C, Ntzani, E, van Wijnen, AJ, Forgetta, V, Ghanbari, M, Logan, JG, Williams, GR, Bassett, JHD, Croucher, PI, Evangelou, E, Uitterlinden, AG, Ackert-Bicknell, CL, Tobias, JH, Evans, DM & Rivadeneira, F 2018, 'Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects' American Journal of Human Genetics, vol. 102, no. 1, pp. 88-102. https://doi.org/10.1016/j.ajhg.2017.12.005

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.; Evans, Daniel S.; Joro, Raimo; Nedeljkovic, Ivana; Zheng, Hou Feng; Zhu, Kun; Atalay, Mustafa; Liu, Ching Ti; Nethander, Maria; Broer, Linda; Porleifsson, Gudmar; Mullin, Benjamin H.; Handelman, Samuel K.; Nalls, Mike A.; Jessen, Leon E.; Heppe, Denise H.M.; Richards, J. Brent; Wang, Carol; Chawes, Bo; Schraut, Katharina E.; Amin, Najaf; Wareham, Nick; Karasik, David; Van der Velde, Nathalie; Ikram, M. Arfan; Zemel, Babette S.; Zhou, Yanhua; Carlsson, Christian J.; Liu, Yongmei; McGuigan, Fiona E.; Boer, Cindy G.; Bønnelykke, Klaus; Ralston, Stuart H.; Robbins, John A.; Walsh, John P.; Zillikens, M. Carola; Langenberg, Claudia; Li-Gao, Ruifang; Williams, Frances M.K.; Harris, Tamara B.; Akesson, Kristina; Jackson, Rebecca D.; Sigurdsson, Gunnar; den Heijer, Martin; van der Eerden, Bram C.J.; van de Peppel, Jeroen; Spector, Timothy D.; Pennell, Craig; Horta, Bernardo L.; Felix, Janine F.; Zhao, Jing Hua; Wilson, Scott G.; de Mutsert, Renée; Bisgaard, Hans; Styrkársdóttir, Unnur; Jaddoe, Vincent W.; Orwoll, Eric; Lakka, Timo A.; Scott, Robert; Grant, Struan F.A.; Lorentzon, Mattias; van Duijn, Cornelia M.; Wilson, James F.; Stefansson, Kari; Psaty, Bruce M.; Kiel, Douglas P.; Ohlsson, Claes; Ntzani, Evangelia; van Wijnen, Andre J.; Forgetta, Vincenzo; Ghanbari, Mohsen; Logan, John G.; Williams, Graham R.; Bassett, J. H.Duncan; Croucher, Peter I.; Evangelou, Evangelos; Uitterlinden, Andre G.; Ackert-Bicknell, Cheryl L.; Tobias, Jonathan H.; Evans, David M.; Rivadeneira, Fernando.

In: American Journal of Human Genetics, Vol. 102, No. 1, 04.01.2018, p. 88-102.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

AU - Medina-Gomez, Carolina

AU - Kemp, John P.

AU - Trajanoska, Katerina

AU - Luan, Jian'an

AU - Chesi, Alessandra

AU - Ahluwalia, Tarunveer S.

AU - Mook-Kanamori, Dennis O.

AU - Ham, Annelies

AU - Hartwig, Fernando P.

AU - Evans, Daniel S.

AU - Joro, Raimo

AU - Nedeljkovic, Ivana

AU - Zheng, Hou Feng

AU - Zhu, Kun

AU - Atalay, Mustafa

AU - Liu, Ching Ti

AU - Nethander, Maria

AU - Broer, Linda

AU - Porleifsson, Gudmar

AU - Mullin, Benjamin H.

AU - Handelman, Samuel K.

AU - Nalls, Mike A.

AU - Jessen, Leon E.

AU - Heppe, Denise H.M.

AU - Richards, J. Brent

AU - Wang, Carol

AU - Chawes, Bo

AU - Schraut, Katharina E.

AU - Amin, Najaf

AU - Wareham, Nick

AU - Karasik, David

AU - Van der Velde, Nathalie

AU - Ikram, M. Arfan

AU - Zemel, Babette S.

AU - Zhou, Yanhua

AU - Carlsson, Christian J.

AU - Liu, Yongmei

AU - McGuigan, Fiona E.

AU - Boer, Cindy G.

AU - Bønnelykke, Klaus

AU - Ralston, Stuart H.

AU - Robbins, John A.

AU - Walsh, John P.

AU - Zillikens, M. Carola

AU - Langenberg, Claudia

AU - Li-Gao, Ruifang

AU - Williams, Frances M.K.

AU - Harris, Tamara B.

AU - Akesson, Kristina

AU - Jackson, Rebecca D.

AU - Sigurdsson, Gunnar

AU - den Heijer, Martin

AU - van der Eerden, Bram C.J.

AU - van de Peppel, Jeroen

AU - Spector, Timothy D.

AU - Pennell, Craig

AU - Horta, Bernardo L.

AU - Felix, Janine F.

AU - Zhao, Jing Hua

AU - Wilson, Scott G.

AU - de Mutsert, Renée

AU - Bisgaard, Hans

AU - Styrkársdóttir, Unnur

AU - Jaddoe, Vincent W.

AU - Orwoll, Eric

AU - Lakka, Timo A.

AU - Scott, Robert

AU - Grant, Struan F.A.

AU - Lorentzon, Mattias

AU - van Duijn, Cornelia M.

AU - Wilson, James F.

AU - Stefansson, Kari

AU - Psaty, Bruce M.

AU - Kiel, Douglas P.

AU - Ohlsson, Claes

AU - Ntzani, Evangelia

AU - van Wijnen, Andre J.

AU - Forgetta, Vincenzo

AU - Ghanbari, Mohsen

AU - Logan, John G.

AU - Williams, Graham R.

AU - Bassett, J. H.Duncan

AU - Croucher, Peter I.

AU - Evangelou, Evangelos

AU - Uitterlinden, Andre G.

AU - Ackert-Bicknell, Cheryl L.

AU - Tobias, Jonathan H.

AU - Evans, David M.

AU - Rivadeneira, Fernando

PY - 2018/1/4

Y1 - 2018/1/4

N2 - 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.

AB - 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.

KW - age-dependent effects

KW - BMD

KW - bone mineral density

KW - CREB3L1

KW - ESR1

KW - fracture

KW - genetic correlation

KW - genome-wide association studies

KW - GWASs

KW - meta-regression

KW - RANKL

KW - total-body DXA

UR - http://www.scopus.com/inward/record.url?scp=85039787162&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2017.12.005

DO - 10.1016/j.ajhg.2017.12.005

M3 - Article

VL - 102

SP - 88

EP - 102

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -