PUBLICATION
Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis
- Authors
- Medina-Gomez, C., Mullin, B.H., Chesi, A., Prijatelj, V., Kemp, J.P., Shochat-Carvalho, C., Trajanoska, K., Wang, C., Joro, R., Evans, T.E., Schraut, K.E., Li-Gao, R., Ahluwalia, T.S., Zillikens, M.C., Zhu, K., Mook-Kanamori, D.O., Evans, D.S., Nethander, M., Knol, M.J., Thorleifsson, G., Prokic, I., Zemel, B., Broer, L., McGuigan, F.E., van Schoor, N.M., Reppe, S., Pawlak, M.A., Ralston, S.H., van der Velde, N., Lorentzon, M., Stefansson, K., Adams, H.H.H., Wilson, S.G., Ikram, M.A., Walsh, J.P., Lakka, T.A., Gautvik, K.M., Wilson, J.F., Orwoll, E.S., van Duijn, C.M., Bønnelykke, K., Uitterlinden, A.G., Styrkársdóttir, U., Akesson, K.E., Spector, T.D., Tobias, J.H., Ohlsson, C., Felix, J.F., Bisgaard, H., Grant, S.F.A., Richards, J.B., Evans, D.M., van der Eerden, B., van de Peppel, J., Ackert-Bicknell, C., Karasik, D., Kague, E., Rivadeneira, F.
- ID
- ZDB-PUB-230705-35
- Date
- 2023
- Source
- Communications biology 6: 691691 (Journal)
- Registered Authors
- Kague, Erika, Karasik, David
- Keywords
- none
- MeSH Terms
-
- Bone Density*/genetics
- Zebrafish/genetics
- Craniosynostoses*/genetics
- Genome-Wide Association Study
- Skull
- Transcription Factors/genetics
- Animals
- PubMed
- 37402774 Full text @ Commun Biol
Citation
Medina-Gomez, C., Mullin, B.H., Chesi, A., Prijatelj, V., Kemp, J.P., Shochat-Carvalho, C., Trajanoska, K., Wang, C., Joro, R., Evans, T.E., Schraut, K.E., Li-Gao, R., Ahluwalia, T.S., Zillikens, M.C., Zhu, K., Mook-Kanamori, D.O., Evans, D.S., Nethander, M., Knol, M.J., Thorleifsson, G., Prokic, I., Zemel, B., Broer, L., McGuigan, F.E., van Schoor, N.M., Reppe, S., Pawlak, M.A., Ralston, S.H., van der Velde, N., Lorentzon, M., Stefansson, K., Adams, H.H.H., Wilson, S.G., Ikram, M.A., Walsh, J.P., Lakka, T.A., Gautvik, K.M., Wilson, J.F., Orwoll, E.S., van Duijn, C.M., Bønnelykke, K., Uitterlinden, A.G., Styrkársdóttir, U., Akesson, K.E., Spector, T.D., Tobias, J.H., Ohlsson, C., Felix, J.F., Bisgaard, H., Grant, S.F.A., Richards, J.B., Evans, D.M., van der Eerden, B., van de Peppel, J., Ackert-Bicknell, C., Karasik, D., Kague, E., Rivadeneira, F. (2023) Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis. Communications biology. 6:691691.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping