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

Carolina Medina-Gomez, Benjamin H. Mullin, Alessandra Chesi, Vid Prijatelj, John P. Kemp, Chen Shochat-Carvalho, Katerina Trajanoska, Carol Wang, Raimo Joro, Tavia E. Evans, Katharina E. Schraut, Ruifang Li-Gao, Tarunveer S. Ahluwalia, M. Carola Zillikens, Kun Zhu, Dennis O. Mook-Kanamori, Daniel S. Evans, Maria Nethander, Maria J. Knol, Gudmar ThorleifssonIvana Prokic, Babette Zemel, Linda Broer, Fiona E. McGuigan, Natasja M. van Schoor, Sjur Reppe, Mikolaj A. Pawlak, Stuart H. Ralston, Nathalie van der Velde, Mattias Lorentzon, Kari Stefansson, Hieab H.H. Adams, Scott G. Wilson, M. Arfan Ikram, John P. Walsh, Timo A. Lakka, Kaare M. Gautvik, James F. Wilson, Eric S. Orwoll, Cornelia M. van Duijn, Klaus Bønnelykke, Andre G. Uitterlinden, Unnur Styrkársdóttir, Kristina E. Akesson, Timothy D. Spector, Jonathan H. Tobias, Claes Ohlsson, Janine F. Felix, Hans Bisgaard, Struan F.A. Grant, J. Brent Richards, David M. Evans, Bram van der Eerden, Jeroen van de Peppel, Cheryl Ackert-Bicknell, David Karasik, Erika Kague, Fernando Rivadeneira

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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.

Original languageEnglish
Article number691
Number of pages12
JournalCommunications Biology
Volume6
Issue number1
DOIs
Publication statusE-pub ahead of print - 4 Jul 2023

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