Autism Genes Converge on Shared Brain Development Issues: New Study
Genetic variations linked to autism spectrum disorder, while diverse in their initial effects on brain development, converge on a shared set of biological processes, a new study reveals. Researchers found that these distinct genetic changes ultimately disrupt neuron maturation, synapse formation and gene regulation within brain organoids grown from cells of autistic individuals.
The study, published last month in Nature, involved the creation of cortical brain organoids – three-dimensional, miniature brain structures grown from stem cells derived from 55 autistic people, including those with known genetic variants and those with idiopathic autism, where the genetic cause is unknown. Researchers monitored the organoids for approximately 100 days, observing how each genetic variant initially impacted development.
Early in development, each genetic variant produced unique effects on the organoids. However, over time, these effects began to coalesce, disrupting common molecular pathways, according to Daniel Geschwind, professor of human genetics, neurology, and psychiatry at the University of California, Los Angeles, and a lead investigator on the study. “The number of lines, the number of variants, the amount of replication—this has never been done before,” Geschwind said.
A core network of genes emerged as a central regulator, influencing downstream changes associated with autism. Manipulating the activity of genes within this network could alter the activity of other genes, suggesting a potential point of intervention. The findings align with observations in other complex conditions, such as cancer, where diverse causes often converge on shared biological mechanisms, Geschwind noted.
While organoids derived from individuals with known genetic variants exhibited this convergence, those from the 11 participants with idiopathic autism did not show the same pattern. Geschwind attributed this to the more subtle genetic effects in these cases, and acknowledged that the sample size was currently too modest to detect convergence with certainty. His team is now expanding the study to include additional variants and more cell lines from individuals with idiopathic autism.
Previous research, including work led by Jürgen Knoblich at the Medical University of Vienna, has utilized brain organoids to study the effects of autism-linked variants. However, Knoblich noted that these earlier studies did not fully consider the influence of an individual’s genetic background. “Truly heroic!” Knoblich commented on the scale of the new study, but cautioned that the current organoid models, primarily composed of excitatory neurons, lack crucial brain cell types like inhibitory interneurons. He suggested that this omission may limit the capture of key biological mechanisms, given the importance of the balance between excitatory and inhibitory neurons in autism.
Kristiina Tammimies, associate professor of medical genetics at the Karolinska Institutet, described the study as a “great compilation of work,” emphasizing its significance in confirming long-held suspicions about shared biological underpinnings of autism. She highlighted the importance of studying the early stages of development, a period that has received less attention compared to later stages.
Geschwind and his team plan to collect molecular, cellular, and electrophysiological measurements from the brain organoids to identify potential biomarkers for drug screening and therapy testing. “We don’t expect that everything is going to converge on the same cell type or the same process, but we hope to identify subsets where one can see a refined convergence,” he said.