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Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis

Medina-Gomez, Carolina ; McGuigan, F.E. LU orcid ; Akesson, K.E. LU and Rivadeneira, F. (2023) In Communications Biology 6(1).
Abstract
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... (More)
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. © 2023, The Author(s). (Less)
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Contribution to journal
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keywords
Animals, Bone Density, Craniosynostoses, Genome-Wide Association Study, Skull, Transcription Factors, Zebrafish, transcription factor, animal, bone density, craniofacial synostosis, genetics, genome-wide association study, meta analysis, skull, zebra fish
in
Communications Biology
volume
6
issue
1
article number
691
publisher
Nature Publishing Group
external identifiers
  • scopus:85164196665
ISSN
2399-3642
DOI
10.1038/s42003-023-04869-0
language
English
LU publication?
yes
id
d6d88938-1310-4cde-8edb-3eea5dc31479
date added to LUP
2023-11-15 11:46:09
date last changed
2023-11-15 11:47:41
@article{d6d88938-1310-4cde-8edb-3eea5dc31479,
  abstract     = {{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. © 2023, The Author(s).}},
  author       = {{Medina-Gomez, Carolina and McGuigan, F.E. and Akesson, K.E. and Rivadeneira, F.}},
  issn         = {{2399-3642}},
  keywords     = {{Animals; Bone Density; Craniosynostoses; Genome-Wide Association Study; Skull; Transcription Factors; Zebrafish; transcription factor; animal; bone density; craniofacial synostosis; genetics; genome-wide association study; meta analysis; skull; zebra fish}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Communications Biology}},
  title        = {{Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis}},
  url          = {{http://dx.doi.org/10.1038/s42003-023-04869-0}},
  doi          = {{10.1038/s42003-023-04869-0}},
  volume       = {{6}},
  year         = {{2023}},
}