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

Y1 - 2018

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 - Adolescent

KW - Age Factors

KW - Animals

KW - Bone Density/genetics

KW - Child

KW - Child, Preschool

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Mice, Knockout

KW - Polymorphism, Single Nucleotide/genetics

KW - Quantitative Trait, Heritable

KW - Regression Analysis

U2 - 10.1016/j.ajhg.2017.12.005

DO - 10.1016/j.ajhg.2017.12.005

M3 - Journal article

C2 - 29304378

VL - 102

SP - 88

EP - 102

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -