Evidence map›Paper›PMID 29883787›Full record

Observational studyBone2018

Genome-wide association study of extreme high bone mass: Contribution of common genetic variation to extreme BMD phenotypes and potential novel BMD-associated genes.

Celia L Gregson, Felicity Newell, Paul J Leo, Graeme R Clark, Lavinia Paternoster, Mhairi Marshall, Vincenzo Forgetta, John A Morris, Bing Ge, Xiao Bao and 10 more

Open access · hybridAbstract readMulticenter StudyObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in Bone, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
29citing papers in PubMed, 1 pooled it
6.3field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

29 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Article
  4. Article
  5. Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2025
    Article
  6. Review
  7. Analysis of Genome-Wide Association Studies.Methods in molecular biology (Clifton, N.J.) · 2025
    Article
  8. Wnt family members regulating osteogenesis and their origins.Journal of bone and mineral metabolism · 2025
    Review
  9. Article
  10. Article
  11. Article
  12. Review
  13. Article
  14. Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023
    Article
  15. Article
  16. Review
  17. Article
  18. Article
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 6 institutions in 3 countries.

Celia L GregsonMusculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. Electronic address: celia.gregson@bristol.ac.uk.
Felicity NewellTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD, Australia.
Paul J LeoTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD, Australia.
Graeme R ClarkTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD, Australia.
Lavinia PaternosterMRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Mhairi MarshallTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD, Australia.
Vincenzo ForgettaDepartment of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
John A MorrisDepartment of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
Bing GeDepartment of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Xiao BaoTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD, Australia.
J H Duncan BassettMolecular Endocrinology Laboratory, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Graham R WilliamsMolecular Endocrinology Laboratory, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Scott E YoultenThe Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Peter I CroucherThe Garvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent's Clinical School, University of New South Wales Medicine, Sydney, New South Wales, Australia.
George Davey SmithMRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
David M EvansMRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
John P KempMRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
Matthew A BrownTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD, Australia.
Jon H TobiasMusculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Emma L DuncanTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD, Australia; Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Translational Research Institute · AUUniversity of Bristol · GBGarvan Institute of Medical Research · AUHammersmith Hospital · GBMcGill University and Génome Québec Innovation Centre · CAJewish General Hospital · CA

Funding

Arthritis Research UK 20000Medical Research Council MC_UU_00011/1Medical Research Council MC_UU_12013/4Versus Arthritis 20000Wellcome Trust 080280/Z/06/ZWellcome Trust 101123
6 · The paper itself

Abstract

backgroundGeneralised 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.

methodsWe 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.

resultsWe 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 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n = 32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable.

conclusionWe report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.

Indexed as

PhenotypeAdultAgedAged, 80 and overAnimalsBone DensityExtracellular Matrix ProteinsFemaleGenetic VariationGenome-Wide Association StudyHumansLumbar VertebraeMaleMiceMice, Inbred C57BLMiddle AgedExtracellular Matrix ProteinsSPON1 protein, humanBone mineral densityEndochondral ossificationNPR3SPON1Wnt signalling

Identifiers

PMID29883787
PMCPMC6086337
OpenAlexW2805552512

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.