Enhanced insights into the genetic architecture of 3D cranial vault shape using pleiotropy-informed GWAS.

Mark D Shriver, Meng Yuan, Joanna Wysocka, John R Shaffer, Sahin Naqvi, Seppe Goovaerts, Hanne Hoskens, Noah Herrick, Susan Walsh, Seth M Weinberg, Peter Claes

Journal: Communications biology 2025;8(1):439

PMID: 40087503

Abstract

Large-scale GWAS studies have uncovered hundreds of genomic loci linked to facial and brain shape variation, but only tens associated with cranial vault shape, a largely overlooked aspect of the craniofacial complex. Surrounding the neocortex, the cranial vault plays a central role during craniofacial development and understanding its genetics are pivotal for understanding craniofacial conditions. Experimental biology and prior genetic studies have generated a wealth of knowledge that presents opportunities to aid further genetic discovery efforts. Here, we use the conditional FDR method to leverage GWAS data of facial shape, brain shape, and bone mineral density to enhance SNP discovery for cranial vault shape. This approach identified 120 independent genomic loci at 1% FDR, nearly tripling the number discovered through unconditioned analysis and implicating crucial craniofacial transcription factors and signaling pathways. These results significantly advance our genetic understanding of cranial vault shape and craniofacial development more broadly.

© 2025. The Author(s).

Address: Department of Human Genetics, KU Leuven, Leuven, Belgium. [email protected].; Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium. [email protected].; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.; Departments of Genetics and Biology, Stanford University School of Medicine, Stanford, CA, USA.; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.; Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium.; Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium.; Department of Cell Biology & Anatomy, Cumming School of Medicine, Alberta Children's Hospital Research, Institute, University of Calgary, Calgary, AB, Canada.; Department of Biology, Indiana University Indianapolis, Indianapolis, IN, USA.; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, KU Leuven, Leuven, Belgium.; Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium.; Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium.; Department of Anthropology, Pennsylvania State University, State College, PA, USA.; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Biology, Indiana University Indianapolis, Indianapolis, IN, USA.; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Anthropology, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Human Genetics, KU Leuven, Leuven, Belgium. [email protected].; Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium. [email protected].; Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium. [email protected].; Murdoch Children's Research Institute, Melbourne, VIC, Australia. [email protected].
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