Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
04 07 2023
04 07 2023
Historique:
received:
20
07
2022
accepted:
25
04
2023
medline:
6
7
2023
pubmed:
5
7
2023
entrez:
4
7
2023
Statut:
epublish
Résumé
Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.
Identifiants
pubmed: 37402774
doi: 10.1038/s42003-023-04869-0
pii: 10.1038/s42003-023-04869-0
pmc: PMC10319806
doi:
Substances chimiques
Transcription Factors
0
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
691Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR000128
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG042124
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG042145
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG042168
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG042140
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG051129
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD058886
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR051124
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG027810
Pays : United States
Organisme : NIAMS NIH HHS
ID : U01 AR066160
Pays : United States
Organisme : NIAMS NIH HHS
ID : RC2 AR058973
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCRR NIH HHS
ID : M01 RR000240
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG042143
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR026314
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG042139
Pays : United States
Informations de copyright
© 2023. The Author(s).
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