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.
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) obse...
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2012-07-01
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| author | Carolina Medina-Gomez John P Kemp Karol Estrada Joel Eriksson Jeff Liu Sjur Reppe David M Evans Denise H M Heppe Liesbeth Vandenput Lizbeth Herrera Susan M Ring Claudia J Kruithof Nicholas J Timpson M Carola Zillikens Ole K Olstad Hou-Feng Zheng J Brent Richards Beate St Pourcain Albert Hofman Vincent W V Jaddoe George Davey Smith Mattias Lorentzon Kaare M Gautvik André G Uitterlinden Robert Brommage Claes Ohlsson Jonathan H Tobias Fernando Rivadeneira |
| author_facet | Carolina Medina-Gomez John P Kemp Karol Estrada Joel Eriksson Jeff Liu Sjur Reppe David M Evans Denise H M Heppe Liesbeth Vandenput Lizbeth Herrera Susan M Ring Claudia J Kruithof Nicholas J Timpson M Carola Zillikens Ole K Olstad Hou-Feng Zheng J Brent Richards Beate St Pourcain Albert Hofman Vincent W V Jaddoe George Davey Smith Mattias Lorentzon Kaare M Gautvik André G Uitterlinden Robert Brommage Claes Ohlsson Jonathan H Tobias Fernando Rivadeneira |
| author_sort | Carolina Medina-Gomez |
| collection | DOAJ |
| description | 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 (r(2) = 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. |
| format | Article |
| id | doaj-art-69c8a149dc7e4012aaa3533e8f95c871 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2012-07-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-69c8a149dc7e4012aaa3533e8f95c8712025-08-20T03:10:41ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-07-0187e100271810.1371/journal.pgen.1002718Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus.Carolina Medina-GomezJohn P KempKarol EstradaJoel ErikssonJeff LiuSjur ReppeDavid M EvansDenise H M HeppeLiesbeth VandenputLizbeth HerreraSusan M RingClaudia J KruithofNicholas J TimpsonM Carola ZillikensOle K OlstadHou-Feng ZhengJ Brent RichardsBeate St PourcainAlbert HofmanVincent W V JaddoeGeorge Davey SmithMattias LorentzonKaare M GautvikAndré G UitterlindenRobert BrommageClaes OhlssonJonathan H TobiasFernando RivadeneiraTo 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 (r(2) = 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002718&type=printable |
| spellingShingle | Carolina Medina-Gomez John P Kemp Karol Estrada Joel Eriksson Jeff Liu Sjur Reppe David M Evans Denise H M Heppe Liesbeth Vandenput Lizbeth Herrera Susan M Ring Claudia J Kruithof Nicholas J Timpson M Carola Zillikens Ole K Olstad Hou-Feng Zheng J Brent Richards Beate St Pourcain Albert Hofman Vincent W V Jaddoe George Davey Smith Mattias Lorentzon Kaare M Gautvik André G Uitterlinden Robert Brommage Claes Ohlsson Jonathan H Tobias Fernando Rivadeneira 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 |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002718&type=printable |
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