TY - JOUR
T1 - Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis
AU - Medina-Gomez, Carolina
AU - Mullin, Benjamin H.
AU - Chesi, Alessandra
AU - Prijatelj, Vid
AU - Kemp, John P.
AU - Shochat-Carvalho, Chen
AU - Trajanoska, Katerina
AU - Wang, Carol
AU - Joro, Raimo
AU - Evans, Tavia E.
AU - Schraut, Katharina E.
AU - Li-Gao, Ruifang
AU - Ahluwalia, Tarunveer S.
AU - Zillikens, M. Carola
AU - Zhu, Kun
AU - Mook-Kanamori, Dennis O.
AU - Evans, Daniel S.
AU - Nethander, Maria
AU - Knol, Maria J.
AU - Thorleifsson, Gudmar
AU - Prokic, Ivana
AU - Zemel, Babette
AU - Broer, Linda
AU - McGuigan, Fiona E.
AU - van Schoor, Natasja M.
AU - Reppe, Sjur
AU - Pawlak, Mikolaj A.
AU - Ralston, Stuart H.
AU - van der Velde, Nathalie
AU - Lorentzon, Mattias
AU - Stefansson, Kari
AU - Adams, Hieab H.H.
AU - Wilson, Scott G.
AU - Ikram, M. Arfan
AU - Walsh, John P.
AU - Lakka, Timo A.
AU - Gautvik, Kaare M.
AU - Wilson, James F.
AU - Orwoll, Eric S.
AU - van Duijn, Cornelia M.
AU - Bønnelykke, Klaus
AU - Uitterlinden, Andre G.
AU - Styrkársdóttir, Unnur
AU - Akesson, Kristina E.
AU - Spector, Timothy D.
AU - Tobias, Jonathan H.
AU - Ohlsson, Claes
AU - Felix, Janine F.
AU - Bisgaard, Hans
AU - Grant, Struan F.A.
AU - Richards, J. Brent
AU - Evans, David M.
AU - van der Eerden, Bram
AU - van de Peppel, Jeroen
AU - Ackert-Bicknell, Cheryl
AU - Karasik, David
AU - Kague, Erika
AU - Rivadeneira, Fernando
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023/7/4
Y1 - 2023/7/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85164196665
U2 - 10.1038/s42003-023-04869-0
DO - 10.1038/s42003-023-04869-0
M3 - Article
C2 - 37402774
AN - SCOPUS:85164196665
SN - 2399-3642
VL - 6
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 691
ER -