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 Thorleifsson; Ivana 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

doi:https://doi.org/10.1038/s42003-023-04869-0

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

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	691
Journal	Communications Biology
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s42003-023-04869-0
Publication status	Published - 1 Dec 2023

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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., ... Rivadeneira, F. (2023). Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis. Communications Biology, 6(1), Article 691. https://doi.org/10.1038/s42003-023-04869-0

@article{3ea160182fd8494fb56fe81e72744299,

title = "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.",

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

note = "Funding Information: The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWAS data. This research has been conducted using the UK Biobank Resource (accession ID: 53641). C.M-G., V.P., J.P.K., M.C.Z., S.R., A.G.U., S.R., U.S., J.H.T., C.O., J.B.R., D.M.E., B.vd.E., J.vdP., C.A-B., D.K., E.K. and F.R. are members of the GEMSTONE CA18139 Cost Action. C.M-G and F.R are supported by ERC-Advanced Grant LEGENDARE [project No. 101021500]. A complete list of acknowledgements per cohort can be found in the Supplementary Material. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

day = "1",

doi = "https://doi.org/10.1038/s42003-023-04869-0",

language = "English",

volume = "6",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Nature Research",

number = "1",

}

Medina-Gomez, C, Mullin, BH, Chesi, A, Prijatelj, V, Kemp, JP, Shochat-Carvalho, C, Trajanoska, K, Wang, C, Joro, R, Evans, TE, Schraut, KE, Li-Gao, R, Ahluwalia, TS, Zillikens, MC, Zhu, K, Mook-Kanamori, DO, Evans, DS, Nethander, M, Knol, MJ, Thorleifsson, G, Prokic, I, Zemel, B, Broer, L, McGuigan, FE, van Schoor, NM, Reppe, S, Pawlak, MA, Ralston, SH, van der Velde, N, Lorentzon, M, Stefansson, K, Adams, HHH, Wilson, SG, Ikram, MA, Walsh, JP, Lakka, TA, Gautvik, KM, Wilson, JF, Orwoll, ES, van Duijn, CM, Bønnelykke, K, Uitterlinden, AG, Styrkársdóttir, U, Akesson, KE, Spector, TD, Tobias, JH, Ohlsson, C, Felix, JF, Bisgaard, H, Grant, SFA, Richards, JB, Evans, DM, 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, vol. 6, no. 1, 691. https://doi.org/10.1038/s42003-023-04869-0

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 - Funding Information: The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWAS data. This research has been conducted using the UK Biobank Resource (accession ID: 53641). C.M-G., V.P., J.P.K., M.C.Z., S.R., A.G.U., S.R., U.S., J.H.T., C.O., J.B.R., D.M.E., B.vd.E., J.vdP., C.A-B., D.K., E.K. and F.R. are members of the GEMSTONE CA18139 Cost Action. C.M-G and F.R are supported by ERC-Advanced Grant LEGENDARE [project No. 101021500]. A complete list of acknowledgements per cohort can be found in the Supplementary Material. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12/1

Y1 - 2023/12/1

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 - http://www.scopus.com/inward/record.url?scp=85164196665&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s42003-023-04869-0

DO - https://doi.org/10.1038/s42003-023-04869-0

M3 - Article

C2 - 37402774

SN - 2399-3642

VL - 6

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 691

ER -

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

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