Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
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.
I: American Journal of Human Genetics, Bind 102, Nr. 1, 2018, s. 88-102.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
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 -
ID: 215458361