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; Peter Claes

doi:10.1038/s41467-023-43237-8

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

Nat Commun. 2023 Nov 16;14(1):7436. doi: 10.1038/s41467-023-43237-8.

Authors

Seppe Goovaerts^{1

2}, Hanne Hoskens^{3

4}, Ryan J Eller⁵, Noah Herrick⁵, Anthony M Musolf⁶, Cristina M Justice^{7

8}, Meng Yuan^{9

3

4}, Sahin Naqvi^{10

11}, Myoung Keun Lee¹², Dirk Vandermeulen^{3

4}, Heather L Szabo-Rogers¹³, Paul A Romitti¹⁴, Simeon A Boyadjiev¹⁵, Mary L Marazita^{12

16}, John R Shaffer^{12

16}, Mark D Shriver¹⁷, Joanna Wysocka^{10

18

19}, Susan Walsh⁵, Seth M Weinberg^{20

21

22}, Peter Claes^{23

24

25

26}

Affiliations

¹ Department of Human Genetics, KU Leuven, Leuven, Belgium. [email protected].
² Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium. [email protected].
³ Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium.
⁴ Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium.
⁵ Department of Biology, Indiana University Indianapolis, Indianapolis, IN, USA.
⁶ Statistical Genetics Section, Computational and Statistical Genomics Branch, NHGRI, NIH, MD, Baltimore, USA.
⁷ Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, NHGRI, NIH, Baltimore, MD, USA.
⁸ Neurobehavioral Clinical Research Section, Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Human Genetics, KU Leuven, Leuven, Belgium.
¹⁰ Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Departments of Genetics and Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Oral and Craniofacial Sciences, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatchewan, Canada.
¹⁴ Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA.
¹⁵ Department of Pediatrics, University of California Davis, Sacramento, CA, USA.
¹⁶ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁷ Department of Anthropology, Pennsylvania State University, State College, PA, USA.
¹⁸ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Department of Oral and Craniofacial Sciences, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
²¹ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
²² Department of Anthropology, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
²³ Department of Human Genetics, KU Leuven, Leuven, Belgium. [email protected].
²⁴ Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium. [email protected].
²⁵ Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium. [email protected].
²⁶ Murdoch Children's Research Institute, Melbourne, VIC, Australia. [email protected].

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.

Publication types

Review

MeSH terms

Animals
Brain / diagnostic imaging
Child
Craniosynostoses* / genetics
Facial Bones
Genome-Wide Association Study*
Humans
Mice
Skull / diagnostic imaging

Abstract

Publication types

MeSH terms

Grants and funding