People who carry common genetic mutations associated with autism tend to have less dense microwiring in their brains, regardless of whether they are actually diagnosed with autism. This study revealed a common genetic structure between the likelihood of autism and the microscopic development of the brain. The study was published in the journal molecular psychiatry.
Autism is a condition that is influenced by vast genetic variations spread across human DNA. Each small genetic difference has only a small effect on its own, but together they determine a person’s potential chance of developing the disease. This type of genetic structure is called polygenic inheritance.
Researchers have been documenting structural differences in the brains of people with autism for years. However, little is known about how the large number of genes associated with autism may influence the physical structure of the brain in the general population. Genetic traits often influence the physical characteristics of an entire population on a sliding scale.
To answer these questions, scientists look for subtle patterns in large databases of health records. University of Cambridge researchers Yuanjun Gu and Varun Warrier led a large team of international scientists to investigate these patterns. They wanted to see if the increased genetic likelihood of autism corresponded to specific measurable differences in brain anatomy.
The researchers analyzed brain imaging and genetic data from two large, independent sources. They examined information from more than 30,000 adults enrolled in the UK Biobank and data from nearly 5,000 children in the Adolescent Brain Cognitive Development Study. Because the researchers used these large datasets, they were able to examine both the fully developed adult brain and the still-developing adolescent brain.
The research team focused on five specific physical characteristics of the brain. Three of these features described the brain’s macrostructure, or large-scale shape. These include the surface area of the outer layers, the average thickness of the cortex, and the average curvature of the brain folds.
The researchers also examined two microscopic features by tracking how water diffuses through brain tissue during magnetic resonance imaging, or MRI scans. One of these microstructural measures is “subcellular volume fraction,” which scientists often use as a reliable indicator of neurite density.
Neurites are projections from the body of a brain cell. These processes include axons, which transmit electrical signals, and dendrites, which receive those signals. By measuring neurite density, researchers can understand how densely packed the brain’s communication lines are in a particular area.
To bridge physical brain scans and genetics, the researchers calculated polygenic scores for all participants. A polygenic score is a single number that summarizes an individual’s total genetic potential for a particular trait, based on millions of different genetic markers. The researchers then used a statistical model to see whether higher autism polygenic scores correlated with differences in brain shape and density.
Results showed a consistent negative association between autism polygenic score and global neurite density. In both adult and child populations, people with more common genetic variants associated with autism tended to have lower neurite density. This association appeared broadly throughout the outer layer of the brain, known as the cortex.
The researchers also observed this relationship deep in the brain. They focused on white matter tracts, which act as long-range communication highways connecting different brain regions. High autism polygenic scores were also associated with reduced neurite density in most of these white matter tracts.
Researchers also analyzed the brain as a networked system. Certain areas act as highly connected hubs, similar to major stations in a rail network. The research team found that the genetic association with low neurite density was more pronounced in these highly connected hub regions compared to the less connected outer edges.
The research team also tested key questions about gender differences. In the general population, boys are diagnosed with autism much more often than girls. Some researchers have hypothesized that biological differences in brain structure between men and women may explain this diagnostic gap.
The researchers ran the statistical model again to look for differences between men and women. They found no statistically significant evidence to suggest that autism genes affect male and female brain structure differently. This result indicates that sex differences in autism diagnosis are likely not due to differences in genetic influences on basic cortical structures.
Although the correlation between genetics and brain structure is strong, researchers stress that correlation is not causation. To test whether autism genes directly cause changes in brain density, the research team used an advanced statistical method called Mendelian randomization.
Mendelian randomization uses genetic data to see whether a change in one trait causes a change in another trait. This is like a naturally occurring randomized clinical trial. The model provided no evidence of direct causality in either direction. The researchers suggest that this genetic link likely stems from a common underlying biological mechanism that simultaneously influences both brain development and behavioral traits.
The researchers note some limitations to their findings. They only analyzed genetic data from individuals of European descent, but this was done to reduce the possibility of statistical error caused by population differences. Research needs to be expanded to diverse populations around the world to see if these patterns persist across different ancestry.
Furthermore, current polygenic scores capture only a small portion of the total possible genetic variance in autism. The specific microscopic associations reported in this study account for only small changes in the overall structure of the brain.
Future studies should also investigate whether reduced neurite density is entirely specific to autism genetics. Similar genetic associations with decreased microscopic brain density have been reported in studies of other diseases such as schizophrenia. Determining whether this structural brain feature is unique to autism or a broader signal for brain development in general will be the next big step for the field.
The study, “Autism polygenic scores are associated with reduced neurite density in adults and children in the general population,” was authored by Yuanjun Gu, Eva Maria-Stauffer, Saashi A. Bedford, APEX Consortium, iPSYCH Autism Consortium, Rafael Romero-Garcia, Jakob Grove, Anders D. Børglum, Hilary Martin, Simon Baron-Cohen, and Richard AI. Bethlehem, and Varun Warrior.
