Global genome-wide association study for cranial vault shape location. The Hierarchical segmentation of the cranial vault shape resulting in 15 cranial vault segments (cyan) in 4 hierarchical levels. B Manhattan plot of genomic associations. For each SNP, the smallest PThe value (CCA, upper tail chi-square) in all 15 cranial vault segments was plotted. Full and dashed horizontal lines represent the entire genome (P <5e−8) and throughout the study (P< 4.37e-9) significance thresholds, respectively. Plausible candidate genes are noted for each significant locus across the genome (n = 30) (Methods). w Number of genetic loci that reach genome-wide significance (P<5e−8; CCA, upper tail chi-square) in each segment of the cranial vault. Credit: Nature Communications(2023). DOI: 10.1038/s41467-023-43237-8
Researchers at the University of Pittsburgh and KU Leuven have discovered a set of genes that influence head shape in humans. These findings, published this week in Nature Communicationshelp explain the diversity of human head shape and may also offer important clues about the genetic basis of diseases that affect the skull, such as craniosynostosis.
By analyzing measurements of the cranial vault – the part of the skull that forms the rounded top of the head and protects the brain – the team identified 30 regions of the genome associated with different aspects of head shape, 29 of which have not been previously reported. .
“Anthropologists have speculated and debated the genetics of cranial vault shape since the early 20th century,” said co-senior author Seth Weinberg, Ph.D., professor of oral and craniofacial sciences at the Pitt School of Dental Medicine and co-director of the Center of Craniofacial and Dental Genetics.
“We knew from certain rare human conditions and animal experiments that genes play an important role in vault size and shape, but very little was known about the genetic basis for typical traits we see in the general population. like what makes someone’s head long and narrow versus short and wide. This study reveals some of the key genes that drive variation in this part of the human body.
According to the researchers, one application for better understanding the factors that drive natural variation in human head shape is to inform paleoanthropology studies, potentially shedding light on the early development of modern humans.
Weinberg and colleagues used magnetic resonance imaging (MRI) scans of more than 6,000 teenagers to extract 3D surfaces corresponding to the cranial vault. After dividing 3D vault surfaces into increasingly smaller anatomical subparts and quantifying the shape of these subparts, they tested more than 10 million genetic variants for evidence of statistical association with vault shape measurements.
“Previous genetic studies of the cranial vault have involved a small number of relatively simple measurements,” Weinberg added. “While these measurements are often easy to obtain, they may fail to capture features that are biologically relevant. Our analysis used an innovative approach capable of describing 3D vault shape in much more comprehensive and nuanced ways. This approach increased our ability to find genetic associations.”
An important finding was that many of the strong associations are close to genes that play key roles in early head and face formation and in regulating bone development. For example, variants within and near the RUNX2 gene, an important player in coordinating skull development, have been associated with multiple aspects of dome shape.
While some genes, including RUNX2, had global effects involving the entire vault, others showed more localized effects that impacted only a specific part of the vault, such as the central forehead.
When researchers compared the 30 genomic regions associated with head shape among participants with European, African and Native American ancestry, they found that the majority of genetic associations were shared between these different ancestral groups.
Although the study focused on healthy participants, the findings could reveal important clues about the biological basis of diseases involving the skullcap, according to Weinberg.
One such condition is craniosynostosis, which occurs when the skull bones fuse too early while the brain is still growing rapidly. Without neurosurgery, craniosynostosis can cause permanent disfigurement, brain damage, blindness and even death. The team showed that variants near three genes associated with dome shape, BMP2, BBS9 and ZIC2, were also associated with craniosynostosis, suggesting that these genes could play a role in the development of the disease.
“This type of study is possible due to the availability of publicly funded resources,” said Weinberg. “The original study that generated these MRI scans is focused on understanding brain development and behavior. By creatively leveraging these resources, we have been able to advance discovery beyond the original scope.”
Seppe Goovaerts et al, Joint multi-ancestry and mixed GWAS reveals the complex genetics behind human cranial vault shape, Nature Communications(2023). DOI: 10.1038/s41467-023-43237-8
Provided by the University of Pittsburgh
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