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


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.

SUBMITTER: Medina-Gomez C 

PROVIDER: S-EPMC10319806 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Medina-Gomez Carolina C   Mullin Benjamin H BH   Chesi Alessandra A   Prijatelj Vid V   Kemp John P JP   Shochat-Carvalho Chen C   Trajanoska Katerina K   Wang Carol C   Joro Raimo R   Evans Tavia E TE   Schraut Katharina E KE   Li-Gao Ruifang R   Ahluwalia Tarunveer S TS   Zillikens M Carola MC   Zhu Kun K   Mook-Kanamori Dennis O DO   Evans Daniel S DS   Nethander Maria M   Knol Maria J MJ   Thorleifsson Gudmar G   Prokic Ivana I   Zemel Babette B   Broer Linda L   McGuigan Fiona E FE   van Schoor Natasja M NM   Reppe Sjur S   Pawlak Mikolaj A MA   Ralston Stuart H SH   van der Velde Nathalie N   Lorentzon Mattias M   Stefansson Kari K   Adams Hieab H H HHH   Wilson Scott G SG   Ikram M Arfan MA   Walsh John P JP   Lakka Timo A TA   Gautvik Kaare M KM   Wilson James F JF   Orwoll Eric S ES   van Duijn Cornelia M CM   Bønnelykke Klaus K   Uitterlinden Andre G AG   Styrkársdóttir Unnur U   Akesson Kristina E KE   Spector Timothy D TD   Tobias Jonathan H JH   Ohlsson Claes C   Felix Janine F JF   Bisgaard Hans H   Grant Struan F A SFA   Richards J Brent JB   Evans David M DM   van der Eerden Bram B   van de Peppel Jeroen J   Ackert-Bicknell Cheryl C   Karasik David D   Kague Erika E   Rivadeneira Fernando F  

Communications biology 20230704 1


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, GLR  ...[more]

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