Researchers at the University of Pittsburgh and KU Leuven have discovered a series of genes that influence head shape in humans. These findings, published this week in Nature communicationsthey help 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 dome shape since the early 20u century,” said co-lead author Seth Weinberg, Ph.D., professor of oral and craniofacial science at Pitt School of Dentistry and co-director of the Center for Craniofacial and Dental Genetics. “We knew from some rare human diseases and animal experiments that genes play an important role in the size and shape of the dome, but very little was known about the genetic basis for typical features we see in the general population, such as what makes one’s head long narrow vs. 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 informing paleoanthropological studies, potentially shedding light on the early development of modern humans.
Weinberg and his colleagues used magnetic resonance (MR) scans from more than 6,000 teenagers to extract three-dimensional surfaces corresponding to the cranial vault. After dividing the three-dimensional surfaces of the vaults into progressively smaller anatomical subdivisions and quantifying the shape of those subdivisions, they screened 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 a novel approach capable of describing three-dimensional vault shape in much more comprehensive and diverse ways. This approach increased our ability to find genetic correlations.”
An important discovery was that many of the strong associations are nearby genes that play key roles in early head and face formation and regulation of bone growth. For example, variations within and near the gene RUNX2an important player in coordinating skull development, were linked to multiple aspects of dome shape.
While some genes, incl RUNX2had global effects involving the entire vault, others showed more localized effects affecting only a specific part of the vault, such as the central front.
When the researchers compared the 30 genomic regions associated with head shape in participants of European, African, and Native American ancestry, they found that the majority of genetic associations were common across these different ancestry 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 too early while the brain is still developing rapidly. Without neurosurgery, craniosynostosis can cause permanent disfigurement, brain damage, blindness, and even death. The team showed that variants near three genes associated with canopy shape, BMP2, BBS9 and ZIC2were also associated with craniosynostosis, suggesting that these genes could play a role in the development of the disease.
“This type of study is possible because of the availability of publicly funded resources,” Weinberg said. “The original study that produced these MRIs is focused on understanding brain development and behavior. By creatively leveraging these resources, we have been able to advance discovery beyond this original field.”
Other authors on the study were Seppe Goovaerts, Hanne Hoskens, Ph.D., Meng Yuan, Dirk Vandermeulen, Ph.D., all from KU Leuven. Ryan J. Eller, Ph.D., Noah Herrick, Ph.D., and Susan Walsh, Ph.D., all of Indiana University-Purdue University Indianapolis. Anthony M. Musolf, Ph.D., and Cristina M. Justice, Ph.D., both of the National Human Genome Research Institute. Sahin Naqvi, Ph.D., and Joanna Wysocka, Ph.D., both of Stanford University. Myoung Keun Lee, Heather L. Szabo-Rogers, Ph.D., Mary L. Marazita, Ph.D., and John R. Shaffer, Ph.D., all of Pitt. Paul A. Romitti, Ph.D., of the University of Iowa. Simeon A. Boyadjiev, MD, of the University of California, Davis; Mark D. Shriver, Ph.D., of Penn State University. and Peter Claes, Ph.D., of KU Leuven and Murdoch Children’s Research Institute.
This research was supported by the National Institute of Dental and Craniofacial Research (R01DE027023, R01DE016886, R03DE031061, and X01HL14053) and the Intrabrain Research Program of the National Human Genome Research Institute, National Institutes of Health