Abstract

The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain. We present supporting evidence of regional localization for several of the identified genes based on expression patterns in the cranial vault bones of E15.5 mice. Overall, our study provides a comprehensive overview of the genetics underlying normal-range cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.

The genetic architecture of normal-range cranial vault shape in humans is poorly understood. Here, the authors extract cranial vault shape from MRI and conduct a multi-ancestry GWAS, identifying 30 independently associated genomic loci of which 29 are novel.

Details

Title
Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape
Author
Goovaerts, Seppe 1   VIAFID ORCID Logo  ; Hoskens, Hanne 2 ; Eller, Ryan J. 3 ; Herrick, Noah 3 ; Musolf, Anthony M. 4 ; Justice, Cristina M. 5 ; Yuan, Meng 6   VIAFID ORCID Logo  ; Naqvi, Sahin 7   VIAFID ORCID Logo  ; Lee, Myoung Keun 8 ; Vandermeulen, Dirk 2 ; Szabo-Rogers, Heather L. 9 ; Romitti, Paul A. 10   VIAFID ORCID Logo  ; Boyadjiev, Simeon A. 11 ; Marazita, Mary L. 12   VIAFID ORCID Logo  ; Shaffer, John R. 12   VIAFID ORCID Logo  ; Shriver, Mark D. 13 ; Wysocka, Joanna 14   VIAFID ORCID Logo  ; Walsh, Susan 15 ; Weinberg, Seth M. 16   VIAFID ORCID Logo  ; Claes, Peter 17   VIAFID ORCID Logo 

1  KU Leuven, Department of Human Genetics, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); University Hospitals Leuven, Medical Imaging Research Center, Leuven, Belgium (GRID:grid.410569.f) (ISNI:0000 0004 0626 3338) 
2  University Hospitals Leuven, Medical Imaging Research Center, Leuven, Belgium (GRID:grid.410569.f) (ISNI:0000 0004 0626 3338); KU Leuven, Department of Electrical Engineering, ESAT/PSI, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
3  Indiana University Indianapolis, Department of Biology, Indianapolis, USA (GRID:grid.5596.f) 
4  Statistical Genetics Section, Computational and Statistical Genomics Branch, NHGRI, NIH, MD, Baltimore, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
5  Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, NHGRI, NIH, Baltimore, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); National Institutes of Health, Neurobehavioral Clinical Research Section, Social and Behavioral Research Branch, National Human Genome Research Institute, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
6  KU Leuven, Department of Human Genetics, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); University Hospitals Leuven, Medical Imaging Research Center, Leuven, Belgium (GRID:grid.410569.f) (ISNI:0000 0004 0626 3338); KU Leuven, Department of Electrical Engineering, ESAT/PSI, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
7  Stanford University School of Medicine, Department of Chemical and Systems Biology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Departments of Genetics and Biology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
8  University of Pittsburgh, Department of Oral and Craniofacial Sciences, Center for Craniofacial and Dental Genetics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
9  University of Saskatchewan, Department of Anatomy, Physiology and Pharmacology, Saskatchewan, Canada (GRID:grid.25152.31) (ISNI:0000 0001 2154 235X) 
10  The University of Iowa, Department of Epidemiology, College of Public Health, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
11  University of California Davis, Department of Pediatrics, Sacramento, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
12  University of Pittsburgh, Department of Oral and Craniofacial Sciences, Center for Craniofacial and Dental Genetics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); University of Pittsburgh, Department of Human Genetics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
13  Pennsylvania State University, Department of Anthropology, State College, USA (GRID:grid.29857.31) (ISNI:0000 0001 2097 4281) 
14  Stanford University School of Medicine, Department of Chemical and Systems Biology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Department of Developmental Biology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Howard Hughes Medical Institute, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
15  Indiana University Indianapolis, Department of Biology, Indianapolis, USA (GRID:grid.168010.e) 
16  University of Pittsburgh, Department of Oral and Craniofacial Sciences, Center for Craniofacial and Dental Genetics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); University of Pittsburgh, Department of Human Genetics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); University of Pittsburgh, Department of Anthropology, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
17  KU Leuven, Department of Human Genetics, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); University Hospitals Leuven, Medical Imaging Research Center, Leuven, Belgium (GRID:grid.410569.f) (ISNI:0000 0004 0626 3338); KU Leuven, Department of Electrical Engineering, ESAT/PSI, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); Murdoch Children’s Research Institute, Melbourne, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X) 
Pages
7436
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-43237-8
ProQuest document ID
2896981682
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.