Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus

Medina-Gomez, Carolina, Kemp, John P., Estrada, Karol, Eriksson, Joel, Liu, Jeff, Reppe, Sjur, Evans, David M., Heppe, Denise H. M., Vandenput, Liesbeth, Herrera, Lizbeth, Ring, Susan M., Kruithof, Claudia J., Timpson, Nicholas J., Zillikens, M.C., Olstad, Ole K., Zheng, Hou-Feng, Richards, J. Brent, St. Pourcain, Beate, Hofman, Albert, Jaddoe, Vincent W. V., Smith, George Davey, Lorentzon, Mattias, Gautvik, Kaare M., Uitterlinden, Andre G., Brommage, Robert, Ohlsson, Claes, Tobias, Jonathan H. and Rivadeneira, Fernando (2012) Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus. PLoS Genetics, 8 7: e1002718.1-e1002718.14. doi:10.1371/journal.pgen.1002718

Author Medina-Gomez, Carolina
Kemp, John P.
Estrada, Karol
Eriksson, Joel
Liu, Jeff
Reppe, Sjur
Evans, David M.
Heppe, Denise H. M.
Vandenput, Liesbeth
Herrera, Lizbeth
Ring, Susan M.
Kruithof, Claudia J.
Timpson, Nicholas J.
Zillikens, M.C.
Olstad, Ole K.
Zheng, Hou-Feng
Richards, J. Brent
St. Pourcain, Beate
Hofman, Albert
Jaddoe, Vincent W. V.
Smith, George Davey
Lorentzon, Mattias
Gautvik, Kaare M.
Uitterlinden, Andre G.
Brommage, Robert
Ohlsson, Claes
Tobias, Jonathan H.
Rivadeneira, Fernando
Title Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2012-01-01
Year available 2012
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1002718
Open Access Status DOI
Volume 8
Issue 7
Start page e1002718.1
End page e1002718.14
Total pages 14
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Language eng
Subject 1311 Genetics
1312 Molecular Biology
1105 Dentistry
1306 Cancer Research
2716 Genetics (clinical)
Abstract To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1×10-11 observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ±500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6×10-31 and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42×10-10) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9×10-16) and rs7801723 (P = 8.9×10-28), also mapping to C7orf58 (r2 = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life.
Keyword Genetics & Heredity
Genetics & Heredity
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID G0600705
ref: 076467
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
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Created: Thu, 20 Mar 2014, 19:11:17 EST by Kylie Hengst on behalf of UQ Diamantina Institute