Autism-Linked Mutations Converge on Shared Early Brain Pathways

UCLA Health researchers have created a comprehensive map showing how eight different genetic mutations associated with autism spectrum disorder affect early brain development, providing new insights into the ways diverse genetic causes may lead to shared features and symptoms of the disorder.

Genetic studies performed over the past two decades have identified more than 100 genes harboring rare mutations linked to autism. This genetic heterogeneity has raised a fundamental question: if autism can be caused by so many different genetic changes, why do individuals with autism often share common features?

The new study, published in the journal Nature, provides new insights by demonstrating that while different mutations affect the developing brain in initially distinct ways, they increasingly impact overlapping molecular pathways as development progresses. 

Modern medicine relies on defining mechanisms that underlie disease susceptibility. Genetics provides a starting point for understanding these mechanisms. Our work extends previous work suggesting that despite the genetic complexity of autism, there may are common biological changes that we can identify and quantify their emergence during early brain development. The hope is that by defining these shared mechanisms that may be able to eventually explain why despite such genetic heterogeneity, patients share common behavioral features."

Dr. Daniel Geschwind, senior author, the Gordon and Virginia MacDonald distinguished professor of Human Genetics, Neurology and Psychiatry at UCLA

The findings are particularly significant because they capture molecular changes during early fetal brain development, which is a critical period when autism risk genes are most active. However, this period has been nearly impossible to study directly in humans. Previous studies have examined postmortem brain tissue collected long after the crucial early developmental events have passed and shown convergent changes. But how they emerge was not known.

To overcome this challenge, the UCLA researchers and their collaborators in the Pasca lab at Stanford University developed brain organoids – laboratory grown clusters of brain cells – consisting of human induced pluripotent stem cell lines. These cortical organoids were derived from stem cell lines from individuals with eight different mutations associated with autism, individuals with idiopathic autism (autism without a known genetic cause) and from neurotypical participants that acted as controls.

Researchers monitored the gene expression of the organoids over 100 days as they developed, which allowed researchers to observe how genetic changes affect brain during the critical early development windows.

Early in development, each genetic form showed distinct molecular signatures. However, as the organoids matured, these different mutations increasingly affected similar biological processes, particularly those involved in neuronal maturation and synapse formation.

"Think of it like different routes leading to similar destinations," said Geschwind. "The mutations start by affecting different aspects of early brain development, but they end up impacting overlapping pathways."

The researchers identified a network of genes involved in regulating gene expression and chromatin remodeling, which is the process by which DNA is packaged and made accessible for reading. This network appears to play a central role in this convergence. Using CRISPR technology to individually reduce the activity of these regulatory genes in neural cells, the team confirmed that many of them control downstream pathways were previously linked to autism.

Notably, the study found few consistent molecular changes in organoids derived from individuals with idiopathic autism, likely reflecting the highly complex genetic architecture of autism that doesn't involve major mutations. This finding underscores the need for much larger studies to understand the more common, polygenic forms of autism.

Geschwind said the study provides a framework for understanding how manifold genetic forms of autism may lead to shared neurobiological features. The identified regulatory network offers potential targets for future research into therapeutic interventions.

"This work demonstrates how stem cell models can help us understand neurodevelopmental conditions during the developmental periods most relevant to disease origins," Geschwind said.

Funding for the study was provided by the National Institutes of Health, the California Institute for Regenerative Medicine, and other funding agencies.