Understanding the Connection Between Genetic Risk and Brain Cell Activity in Autism Spectrum Disorder


Over the course of 15 years, epigenetic and transcriptional analysis of postmortem brain samples have revealed underlying molecular differences.

Researchers have observed the first link between genetic risk of autism spectrum disorder (ASD) and cellular activity across various areas of the brain, in a study led by the University of California Los Angeles (UCLA) Health. The results offer physicians a deeper understanding of the molecular changes consistent with ASD, providing insight into the underlying cause of the disorder and enhanced approaches to treatment for patients.

autism gene expression

Although the cause of ASD is not well understood, there is a growing area of research focusing on the interaction of rare gene changes with environmental factors. Image Credits: © Prostock-studio - stock.adobe.com

ASD is a bio-neurological developmental disability that affects brain development, altering the functioning of brain regions involved in social interaction, cognitive processes, and communication. According to the National Autism Association, ASD affects 1 in 36 children with males being 4 times as likely to have autism compared with females. Individuals with autism often present with various comorbidities such as sensory integration dysfunction, feeding disorders, behavior disorders, epilepsy, and autoimmune disorders, among others, which impact their overall wellness and quality of life. However, ASD is very treatable and early childhood intervention is key to maximize developmental and wellness outcomes for patients.1

The study results out of UCLA Health aim to better understand the driving mechanisms behind molecular differences and genetic susceptibility at the cellular level, mapping genes across different brain regions at various stages of development. The study authors hypothesized that a deep molecular analysis at the single-cell level would reveal changes in cortical cell types and circuits to enable identification of altered regulating factors in neural pathways.2

In the study, more than 80,000 nuclei from postmortem brain tissue were isolated from a cohort of 66 individuals ranging in age from 2 to 60. The group included 33 individuals diagnosed with ASD with a control of 30 neurotypical individuals. Using single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) in a large ASD and control (CTL) cohort, study authors identified the cell-type specific changes and cellular regulatory networks disrupted by genetic risk factors.2,3

On average, more than 10,000 cells per individual and more than 1860 genes per cell were used to identify all 26 major cortical cell types, including neurons and glial cells. Study authors recognized multiple cell types in activated states, such as microglia (MG), oligodendrocytes, astrocytes (ASTROs), and blood-brain barrier cells, which may influence neuroinflammation and immune dysregulation in ASD.2

The results show that changes to cell composition in ASD were minor, involving an increase in activated MG and ASTRO states. Alternatively, changes observed in gene expression were significant. Using snRNA-sep, snATAC-seq, and spatial transcriptomics, the study authors analyzed gene expression changes and detected 2166 down-regulated and 1319 up-regulated genes across 35 cell types, of which most were cell type-specific.2

Furthermore, the study authors identified the regulatory networks responsible for altered gene expression in specific cortical layers of the brain. The superficial cortical layers exhibited high concentrations of MG, ASTROs, and somatostatin interneurons, suggesting increased activation or volume of specific cell types in certain regions of the cortex. Additionally, some neurons transmitting signals within and between brain hemispheres displayed a substantial down-regulation of genes related to synaptic function, along with an up-regulation of genes associated with stress-response and proinflammatory pathways.2,3

Analysis of the regulatory networks revealed a high expression of genes associated with increased risk of ASD in transcription factor networks, which is a system of interacting proteins that regulate gene expression and inhibition. These results are the first indication of a connection between changes occurring in the brain and underlying genetic causes, creating an opportunity for clinicians to develop new therapeutic approaches for individuals with ASD.

Although the cause of ASD is not well understood, there is a growing area of research focusing on the interaction of rare gene changes with environmental factors. Over the course of 15 years, epigenetic and transcriptional analysis of postmortem brain samples have revealed underlying molecular differences, which reflect the up-regulation of immune signaling genes, down-regulation of neuronal markers and synaptic genes, and a blunting of gene expression signatures of cortical regional identity evident in ASD.2 However, further research is needed to gain a deeper understanding of the driving mechanisms behind ASD to enhance patient outcomes, quality-of-life, and combat the misconceptions associated with the condition.

1. Autism fact sheet - national autism association. National Autism Association. January 27, 2012. Accessed June 5, 2024. https://nationalautismassociation.org/resources/autism-fact-sheet/?gad_source=1&gclid=CjwKCAjwmYCzBhA6EiwAxFwfgFGNOfNDb_jSiXkOFeQea68TleDzzhxRrJfsG1nGMjp5rI4YtDCZCxoCYWMQAvD_BwE
2. Wamsley B, Bicks L, Cheng Y, et al. Molecular cascades and cell type–specific signatures in ASD revealed by single-cell genomics. Science. May 24, 2024. doi:10.1126/science.adh2602
3. Groundbreaking study connects genetic risk for autism to changes observed in the brain. EurekAlert. May 23, 2024. Accessed June 5, 2024. https://www.eurekalert.org/news-releases/1045872
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