Researchers have found that the wide variety of symptoms found in people with autism can be traced back to certain genetic mutations, with the more damaging mutations leading to worse disease outcomes. Their findings are published in the journal Nature Neuroscience.
The study, conducted by Columbia University Medical Center, involved a large-scale analysis of hundreds of patients and nearly 1000 genes. Researchers have identified hundreds of genes that, when mutated, raise the risk of a person developing autism spectrum disorder (ASD), and these mutations can lead to a variety of symptoms.
“If we can understand how different mutations lead to different features of ASD, we may be able to use patients’ genetic profiles to develop accurate diagnostic and prognostic tools and perhaps personalize treatment,” said senior author Dennis Vitkup, Ph.D., associate professor of systems biology and biomedical informatics at Columbia University’s College of Physicians & Surgeons.
To explore the connection between genetic mutations and autism traits, the researchers analyzed genetic and clinical data on hundreds of patients with ASD from the Simons Simplex Collection. They discovered that the more damaging genetic mutations usually lead to worse disease outcomes. “It looks as if high-IQ autism cases are usually triggered by milder mutations,” said Vitkup.
Autistic people with low-verbal or nonverbal IQs usually had mutations in genes that played a more active role in the brain; and high-IQ individuals were less likely to have mutations that completely shut down genes. In fact, mutations that only partially damage normal gene function in the brain appear to be strongly linked with high-functioning autism cases.
Individual gene mutations also account for the gender differences found in autism. Although ASD is much more common in males, females with ASD are more likely to fall on the severe end of the spectrum.
The findings showed that the genes mutated in females generally had greater activity throughout the brain than those mutated in males. Extremely damaging ASD mutations in girls on average are found in genes that are almost twice as active as typical genes in normal brains.
“These patterns are consistent with the idea that there are mechanisms that protect females,” said Vitkup.
“Most often, only when a mutation hits a highly active gene do we see symptoms in females. Given that the inherent differences in gene activity in male and female brains are typically on the order of a few percent, these findings are quite remarkable.”
Certain neurons appear to be more affected than others. The researchers found strong effects in cortical and striatal neurons that form a circuit that controls repetitive motions and behaviors, such as rocking, an insistence on sameness, and restricted interests, which are common in people with ASD.
“There are many hypotheses about the types of neurons and circuits involved in autism, but by using unbiased genome-wide approaches, like the one used in this study, one can understand which neurons are the most important and explain the core features we see in people with ASD,” said Vitkup.
“Identifying the circuits involved is the next step in understanding autism,” he said. “Huge progress has been made in the last five years: We and our colleagues have now identified multiple affected genes, and we are coming to a consensus about how the genes work together in biological networks.
“Now, based on the affected genes, we are identifying affected cell types and brains circuits and trying to connect them to disease outcomes in individual patients.”