Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape

Seppe Goovaerts (), Hanne Hoskens, Ryan J. Eller, Noah Herrick, Anthony M. Musolf, Cristina M. Justice, Meng Yuan, Sahin Naqvi, Myoung Keun Lee, Dirk Vandermeulen, Heather L. Szabo-Rogers, Paul A. Romitti, Simeon A. Boyadjiev, Mary L. Marazita, John R. Shaffer, Mark D. Shriver, Joanna Wysocka, Susan Walsh, Seth M. Weinberg () and Peter Claes ()
Additional contact information
Seppe Goovaerts: KU Leuven
Hanne Hoskens: University Hospitals Leuven
Ryan J. Eller: Indiana University Indianapolis
Noah Herrick: Indiana University Indianapolis
Anthony M. Musolf: Statistical Genetics Section, Computational and Statistical Genomics Branch, NHGRI, NIH, MD
Cristina M. Justice: Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, NHGRI, NIH
Meng Yuan: KU Leuven
Sahin Naqvi: Stanford University School of Medicine
Myoung Keun Lee: University of Pittsburgh
Dirk Vandermeulen: University Hospitals Leuven
Heather L. Szabo-Rogers: University of Saskatchewan
Paul A. Romitti: The University of Iowa
Simeon A. Boyadjiev: University of California Davis
Mary L. Marazita: University of Pittsburgh
John R. Shaffer: University of Pittsburgh
Mark D. Shriver: Pennsylvania State University
Joanna Wysocka: Stanford University School of Medicine
Susan Walsh: Indiana University Indianapolis
Seth M. Weinberg: University of Pittsburgh
Peter Claes: KU Leuven

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43237-8

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