Summary: New research shows that children with a high genetic susceptibility to schizophrenia display a distinct decrease in frontal cortical surface area during early adolescence, while children with low genetic susceptibility exhibit regional expansion in the same areas. These findings offer early in vivo evidence that genetic liability for schizophrenia can alter brain development long before clinical symptoms typically appear.
The study analyzed repeated brain imaging and genetic data from more than 6,000 young people to map how polygenic risk influences brain structure over time. Results point to early adolescence as a critical window when genetic risk for schizophrenia begins to shape neurodevelopmental trajectories, particularly in frontal cortical regions.
Key Research Findings
- A critical developmental window: Early adolescence (roughly ages 9–14) is the period when genetic influences on brain structure began to diverge between high- and low-risk groups.
- Surface area versus thickness: The study focused on cortical surface area, a phenotype that is genetically separable from cortical thickness and may be a more sensitive indicator of genetically driven neurodevelopmental change.
- Specific frontal regions implicated: Children with higher genetic risk for schizophrenia showed decreases in surface area in the caudal middle frontal and superior frontal regions, whereas children with lower risk showed the expected increases in these same regions during adolescence.
- Unique pattern for schizophrenia: Genetic liability for ADHD and educational attainment was associated with persistently smaller or larger surface areas, respectively, but only schizophrenia polygenic risk scores (PGSs) were linked to a dynamic divergence in development over time.
- Supports neurodevelopmental origins: The observed diverging trajectories are consistent with the idea that schizophrenia has neurodevelopmental roots that begin years before clinical onset.
Source: Elsevier
The findings, published in the journal Biological Psychiatry, refine our understanding of when and how genetic risk for schizophrenia starts to affect brain structure. Because more than 60% of psychiatric disorders first appear before age 25 and many show early, gradual signs, identifying the timing of brain changes is essential for developing preventive strategies.
Lead investigator Henning Tiemeier, MA, MD, PhD, Department of Social and Behavioral Sciences at Harvard T.H. Chan School of Public Health, emphasizes the importance of timing: “Pinpointing when genetic risks begin to manifest in the brain could offer crucial clues for early diagnosis and intervention.”
This longitudinal analysis pooled data from the Adolescent Brain Cognitive Development (ABCD) Study in the United States and the Generation R Study in the Netherlands. The sample included 6,228 participants of European descent, with baseline ages around 9–10 years and follow-up spanning two to four years. Across repeated MRI sessions, researchers analyzed 9,720 brain images alongside genetic profiles to chart how polygenic liability for several traits related to structural brain changes over time.
Co-lead investigator Ryan Muetzel, PhD, Department of Child and Adolescent Psychology and Psychiatry at Erasmus University Medical Center Rotterdam, notes the importance of focusing on surface area: “Surface area and thickness are largely genetically separable phenotypes and follow distinct developmental trajectories. Surface area often shows stronger heritability and may therefore be a particularly sensitive marker of genetically driven neurodevelopmental processes relevant to psychiatric disorders.” First author Bing Xu, MSc, adds that these results point to surface area as a promising measure for detecting early, genetically influenced brain changes.
The study also examined polygenic scores for ADHD, autism spectrum disorder, major depressive disorder, and educational attainment. While higher PGSs for educational attainment correlated with consistently larger surface area and higher ADHD PGSs with consistently smaller surface area across time, these patterns were static rather than dynamically divergent. By contrast, schizophrenia PGSs predicted a change in trajectory: the same frontal regions that expanded in low-risk children decreased in surface area among high-risk children during early adolescence.
Tiemeier reflects on the clarity of the patterns: “We were struck by how clearly we could see these diverging developmental patterns for schizophrenia in the brain over time. The fact that these differences appeared so early and so consistently was notable.”
The investigators emphasize that the study detected relatively small effect sizes, a common outcome in large-scale neuroimaging genetics research. While the group-level findings are robust and informative for models of disease origin, additional research is required before these measures can be used to predict outcomes for individual children.
John Krystal, MD, Editor of Biological Psychiatry, highlights the broader implications: “The developmental emergence of altered brain structure and function is central to the development of schizophrenia. Early neurodevelopmental divergence from the general population may have implications for social and cognitive development and underscores the importance of genetic risk on the timing of these developmental changes.”
Key Questions Answered
Q: Does a smaller brain area in these regions mean a child will definitely develop schizophrenia?
A: No. The study found group-level patterns, but effect sizes were relatively small. These results are valuable for understanding disease origins rather than providing a definitive prognosis for individual children.
Q: Why is early adolescence important for this research?
A: Early adolescence is a time of rapid structural and functional brain change and coincides with the age range when many psychiatric disorders begin to emerge, making it an ideal period to study early divergence in neurodevelopment.
Q: How could these findings influence future treatments?
A: By identifying when genetic risk starts to alter brain development, clinicians and researchers can better determine optimal windows for preventive interventions and move psychiatry toward earlier, prevention-focused care.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional context was added by staff to clarify the study’s methods and implications.
About this genetics and schizophrenia research news
Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy, Elsevier
Image credit: Neuroscience News
Original Research: Open access. “Genetic Susceptibility to Schizophrenia and the Onset of Brain Developmental Change in Adolescence” by Bing Xu, Annet Dijkzeul, Yingzhe Zhang, Isabel K. Schuurmans, Charlotte A.M. Cecil, Phil H. Lee, Ryan L. Muetzel, and Henning Tiemeier. Biological Psychiatry. DOI: 10.1016/j.biopsych.2026.03.989
Abstract
Genetic Susceptibility to Schizophrenia and the Onset of Brain Developmental Change in Adolescence
Background
Early neurodevelopmental signs of genetic vulnerability are central to understanding the origins of psychiatric disorders and guiding early intervention. However, the timing of when genetic risks manifest in brain structure has been unclear.
Methods
The analysis combined two large neurodevelopmental cohorts—the ABCD Study and the Generation R Study—to examine repeated brain imaging in 6,228 individuals of European descent (mean baseline age ~10 years) with follow-up ranging from two to four years. Whole-brain vertexwise linear mixed models tested associations between polygenic scores for ADHD, autism spectrum disorder, schizophrenia, major depressive disorder, and educational attainment and longitudinal brain morphology.
Results
Children with low genetic susceptibility to schizophrenia showed expected increases in cortical surface area in caudal middle and superior frontal regions during early adolescence. Children with higher schizophrenia PGSs showed decreases in these same regions, indicating divergent neurodevelopmental trajectories that emerge in this period. Other psychiatric PGSs did not show dynamic associations with brain change; however, higher educational attainment PGSs correlated with persistently larger surface area and higher ADHD PGSs with persistently smaller surface area across time.
Conclusions
The findings suggest that genetic susceptibility to schizophrenia begins to affect brain structure in early adolescence, producing dynamic changes that could serve as early biomarkers and inform the timing of preventive interventions.