Study finds 1,200-plus autism-risk genes converge on two brain states

More than 1,200 genes have been linked to autism spectrum disorder, but new research published in Science on September 18, 2026, reveals that this vast genetic diversity funnels into just two opposing molecular states in the brain — a finding that could reshape how scientists study and eventually treat the condition.medicalxpress

A team led by Professor Kim Eunjoon at the Institute for Basic Science's Center for Synaptic Brain Dysfunctions analyzed 1,008 RNA sequencing profiles from the prefrontal cortex of 17 genetically engineered mouse lines, each carrying a different autism-risk mutation. Rather than finding hundreds of distinct disruption patterns, the researchers identified a recurring molecular divide: one group of mice showed reduced expression of genes involved in synaptic communication alongside increased chromatin and RNA processing activity, while a second group displayed the mirror-image pattern.neurosciencenews+2

A Molecular Seesaw Shaped by Context

The groupings were not fixed by genetics alone. In seven of the 17 mouse lines, males and females carrying the same mutation sorted into opposite molecular groups. The classifications also shifted across developmental stages and were far less pronounced in the hippocampus than in the prefrontal cortex, indicating that sex, age, and brain region all shape the molecular outcome of a given mutation.neurosciencenews+1

Single-nucleus RNA sequencing of roughly one million individual cells from 205 mice confirmed these patterns arise from coordinated, network-wide shifts across diverse neuronal and glial cell populations rather than from a single defective cell type.news-medical+1

"Many different genetic mutations converge into a limited number of molecular brain states, providing a framework for understanding autism at the level of shared biology rather than individual genes," said co-corresponding author Dr. Bae Mihyun.medicalxpress

Drug Responses Diverge by Molecular Profile

The two groups also responded differently to early postnatal exposure to fluoxetine and lithium. Group 1 models showed more consistent normalization of gene expression toward control patterns, while Group 2 displayed variable, heterogeneous responses. Neither drug reversed underlying shifts in cell-type proportions, suggesting their effects were limited to specific transcriptional circuits.biz.chosun+2

When the researchers examined prefrontal cortex data from 40 autistic individuals and 17 neurotypical controls, they detected two analogous human subgroups with opposing synaptic gene activity patterns, though human samples showed more prominent immune and inflammatory signals. The authors caution that the findings cannot yet be used to diagnose clinical subtypes or guide medication choices.neurosciencenews+1

"Instead of asking which gene is mutated, we asked whether different mutations produce common molecular patterns in the brain," said Kim Eunjoon. "That perspective revealed a surprising level of convergence across genetically distinct forms of autism."medicalxpress