The roots of autism and schizophrenia may lie in the earliest weeks of brain development.
Researchers at the University of Exeter examined nearly 1,000 donated human brains and found that most changes to DNA chemistry happened before birth, particularly in genes tied to autism and schizophrenia.
Early brain changes tied to autism and schizophrenia
The cortex is the part of the brain responsible for thought, memory, perception and behavior. Its development depends on a precise timetable, guided by both genes and chemical tags that sit on DNA. These tags, known as epigenetic marks, influence whether a gene is switched on or off. One of the most studied marks is DNA methylation. Shifts in methylation help brain cells specialize, and problems in this process are linked to disorders. Mutations in genes such as MECP2, which interprets methylation marks, cause severe neurodevelopmental conditions.
Research has shown that methylation in the brain undergoes rapid changes during fetal development. However, past studies have been limited by a low number of samples, or they have focused on a narrow age range, usually in mid-gestation or later, meaning it couldn’t be seen how methylation patterns evolve across the entire lifespan. Another gap is that most studies measured average signals from mixed brain tissue, which made it difficult to see how methylation differs between cell types, such as neurons and supporting glial cells.
Conditions such as autism and schizophrenia are thought to begin with changes in the developing cortex long before symptoms appear. To better understand these links, the team set out to create the most detailed map so far of DNA methylation across human brain development, from 6 weeks after conception through to 108 years of age.
Mapping DNA methylation in the cortex
The researchers studied cortex tissue from almost 1,000 individuals. Instead of focusing on one stage of life, they spanned the entire course. They also developed a method to separate neurons, the cortex’s main signaling cells, from other types such as astrocytes.
The vast majority of DNA methylation changes took place before birth. Over 50,000 sites across the genome showed developmental shifts. By mid-gestation, many of these changes had already stabilized, and postnatal changes were slower and often moved in the opposite direction.
Some genes showed non-linear trajectories, with “switch points” – sharp shifts in DNA methylation levels – between 12–15 weeks after conception. These were linked to processes such as synapse formation and neuron projection.
Neurons and non-neurons also showed distinct methylation patterns, with neuron-specific marks already present long before cells had fully matured.
Many genes connected to autism and schizophrenia showed dynamic methylation during fetal development. Schizophrenia risk variants, identified through large genetic studies, were particularly enriched in neuron-specific sites. Autism showed a similar pattern, though weaker in genome-wide analyses, likely because fewer large-scale datasets exist.
Implications for autism and schizophrenia research
The findings highlight the prenatal period as a critical window in shaping the cortex. Most of the chemical changes occurred before birth, suggesting that disruptions during this time could contribute to autism and schizophrenia. The dataset now provides a reference map for future research, helping scientists test how genetic risks interact with early brain development.
“By analyzing how chemical changes to DNA shape the brain across the human lifespan, we’ve uncovered important clues about why neurodevelopmental conditions like autism and schizophrenia may develop. Our findings highlight that their roots may lie very early on in brain development,” said first author Alice Franklin, a graduate research assistant at the University of Exeter.
However, access to later-stage fetal samples was restricted, and the technology used only covered part of the genome and could not distinguish between different chemical DNA marks. The cell-sorting approach separated neurons from other cells but did not capture the full diversity of cortical cell types.
Future work will focus on sequencing-based methods for wider coverage, studying other forms of methylation and analyzing more brain regions.
“This work gives us a clearer picture of the biological processes guiding brain development and how these differ across cell types. In the long term, this could help us move closer to understanding the mechanisms underpinning neurodevelopmental conditions,” said corresponding author Dr. Jonathan Mill, a professor of epigenomics and the head of the Complex Disease Epigenomics Group at the University of Exeter.
Reference: Franklin A, Davies JP, Clifton NE, et al. Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex. Cell Genomics. 2025:101010. doi: 10.1016/j.xgen.2025.101010
This article is a rework of a press release issued by the University of Exeter. Material has been edited for length and content.