Communications Biology (Jul 2023)
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
Affiliations
- Carolina Medina-Gomez
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Benjamin H. Mullin
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital
- Alessandra Chesi
- Division of Human Genetics, Children’s Hospital of Philadelphia
- Vid Prijatelj
- Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center Rotterdam
- John P. Kemp
- Institute for Molecular Bioscience, The University of Queensland
- Chen Shochat-Carvalho
- Azrieli Faculty of Medicine, Bar-Ilan University
- Katerina Trajanoska
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Carol Wang
- School of Women’s and Infants’ Health, University of Western Australia
- Raimo Joro
- Institute of Biomedicine, Physiology, University of Eastern Finland
- Tavia E. Evans
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam
- Katharina E. Schraut
- Centre for Global Health Research, Usher Institute, University of Edinburgh
- Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Centre
- Tarunveer S. Ahluwalia
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- M. Carola Zillikens
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Kun Zhu
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital
- Dennis O. Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Centre
- Daniel S. Evans
- California Pacific Medical Center Research Institute
- Maria Nethander
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg
- Maria J. Knol
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam
- Gudmar Thorleifsson
- deCODE Genetics/Amgen
- Ivana Prokic
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam
- Babette Zemel
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania
- Linda Broer
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Fiona E. McGuigan
- Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University
- Natasja M. van Schoor
- Department of Epidemiology and Data Science, Amsterdam UMC
- Sjur Reppe
- Department of Plastic and Reconstructive Surgery, Oslo University Hospital
- Mikolaj A. Pawlak
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam
- Stuart H. Ralston
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- Nathalie van der Velde
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Mattias Lorentzon
- Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
- Kari Stefansson
- deCODE Genetics/Amgen
- Hieab H. H. Adams
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam
- Scott G. Wilson
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital
- M. Arfan Ikram
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam
- John P. Walsh
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital
- Timo A. Lakka
- Institute of Biomedicine, Physiology, University of Eastern Finland
- Kaare M. Gautvik
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital
- James F. Wilson
- Centre for Global Health Research, Usher Institute, University of Edinburgh
- Eric S. Orwoll
- Department of Public Health & Preventive Medicine, Oregon Health & Science University
- Cornelia M. van Duijn
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam
- Klaus Bønnelykke
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- Andre G. Uitterlinden
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Unnur Styrkársdóttir
- deCODE Genetics/Amgen
- Kristina E. Akesson
- Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University
- Timothy D. Spector
- Department of Twin Research & Genetic Epidemiology, King’s College London
- Jonathan H. Tobias
- MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol
- Claes Ohlsson
- Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
- Janine F. Felix
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Hans Bisgaard
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- Struan F. A. Grant
- Division of Human Genetics, Children’s Hospital of Philadelphia
- J. Brent Richards
- Department of Twin Research & Genetic Epidemiology, King’s College London
- David M. Evans
- Institute for Molecular Bioscience, The University of Queensland
- Bram van der Eerden
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Jeroen van de Peppel
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam
- Cheryl Ackert-Bicknell
- Department of Orthopedics, University of Colorado
- David Karasik
- Azrieli Faculty of Medicine, Bar-Ilan University
- Erika Kague
- The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol
- Fernando Rivadeneira
- Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center Rotterdam
- DOI
- https://doi.org/10.1038/s42003-023-04869-0
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 12
Abstract
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.
