Suite of genes affect head shape in humans

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Researchers at the University of Pittsburgh and KU Leuven have discovered a number of genes that affect head shape in humans. These results, published this week in Nature communicationhelp explain the diversity of human head shapes and may also provide important clues about the genetic basis of conditions affecting 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 reported before.

“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 for Craniofacial and Dental Genetics. “We knew from certain rare human conditions and animal studies that genes play an important role in the size and shape of the vaults, but very little was known about the genetic basis of typical traits we see in the general population, such as what makes a person’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 of better understanding the factors driving natural variation in human head shape is to inform paleoanthropological studies, potentially shedding light on the early evolution of modern humans.

Weinberg and colleagues used magnetic resonance (MR) scans from more than 6,000 young people to extract 3D surfaces corresponding to the cranial vault. After dividing the 3D vault surfaces into incrementally smaller anatomical subdivisions and quantifying the shape of those subdivisions, they tested more than 10 million genetic variants for evidence of statistical association with measures of vault shape.

“Previous genetic studies of the cranial vault involved a small number of relatively simple measures,” Weinberg added. “Although such measures are often easy to obtain, they may not capture features that are biologically relevant. Our analysis used an innovative approach that was able to describe 3D vault shape in much more comprehensive and nuanced ways. This approach increased our ability to find genetic associations.”

An important discovery was that many of the strong associations are near genes that play key roles in the early formation of the head and face and regulation of bone development. For example, variants in and near the gene RUNX2an important player in coordinating the development of the skull, was associated with several aspects of vault shape.

While some genes, e.g RUNX2had global effects involving the entire vault, others showed more localized effects affecting only a specific part of the vault, such as the central forehead.

When the researchers compared the 30 genomic regions associated with head shape across participants with European, African, and Native American ancestry, they found that the majority of genetic associations were shared across these different ancestral groups.

Although the study focused on healthy participants, the findings may reveal important clues about the biological basis of diseases involving the cranial vault, according to Weinberg.

One of these conditions is craniosynostosis, which occurs when the bones of the skull fuse together prematurely 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 vault shape, BMP2, BBS9 and ZIC2was also associated with craniosynostosis, suggesting that these genes could play a role in the development of the disease.

“This kind of study is possible because of the availability of publicly funded resources,” Weinberg said. “The original study that generated these MRIs is focused on understanding brain development and behavior. By creatively utilizing these resources, we have been able to advance discovery beyond the original scope.”

Reference: Goovaerts S, Hoskens H, Eller RJ, et al. Shared multi-ancestry and admixed GWAS reveal the complex genetics of human cranial vault shape. Night Commun. 2023;14(1):7436. doi: 10.1038/s41467-023-43237-8

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