Imperial College London
Alternate

Professor Duncan Bassett

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Professor of Endocrinology
 
 
 
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Contact

 

+44 (0)20 3313 4613d.bassett Website

 
 
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Location

 

10N6 Commomwealth BuildingHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Gregson:2018:10.1016/j.bone.2018.06.001,
author = {Gregson, CL and Newell, F and Leo, PJ and Clark, GR and Paternoster, L and Marshall, M and Forgetta, V and Morris, JA and Ge, B and Bao, X and Duncan, Bassett JH and Williams, GR and Youlten, SE and Croucher, PI and Davey, Smith G and Evans, DM and Kemp, JP and Brown, MA and Tobias, JH and Duncan, EL},
doi = {10.1016/j.bone.2018.06.001},
journal = {Bone},
pages = {62--71},
title = {Genome-wide association study of extreme high bone mass: contribution of common genetic variation to extreme BMD phenotypes and potential novel BMD-associated genes},
url = {http://dx.doi.org/10.1016/j.bone.2018.06.001},
volume = {114},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BACKGROUND: Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. METHODS: We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n=240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n=1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n=900), with Z-scores -1.5 to -4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. RESULTS: We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF]=0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF=0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-β regulated BMP-driven osteoblast differentiation. Rs9292469
AU  - Gregson,CL
AU  - Newell,F
AU  - Leo,PJ
AU  - Clark,GR
AU  - Paternoster,L
AU  - Marshall,M
AU  - Forgetta,V
AU  - Morris,JA
AU  - Ge,B
AU  - Bao,X
AU  - Duncan,Bassett JH
AU  - Williams,GR
AU  - Youlten,SE
AU  - Croucher,PI
AU  - Davey,Smith G
AU  - Evans,DM
AU  - Kemp,JP
AU  - Brown,MA
AU  - Tobias,JH
AU  - Duncan,EL
DO  - 10.1016/j.bone.2018.06.001
EP  - 71
PY  - 2018///
SN  - 8756-3282
SP  - 62
TI  - Genome-wide association study of extreme high bone mass: contribution of common genetic variation to extreme BMD phenotypes and potential novel BMD-associated genes
T2  - Bone
UR  - http://dx.doi.org/10.1016/j.bone.2018.06.001
UR  - https://www.ncbi.nlm.nih.gov/pubmed/29883787
UR  - http://hdl.handle.net/10044/1/60703
VL  - 114
ER  -
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