Summary: New research reveals that children with a high genetic susceptibility to schizophrenia exhibit a distinct decrease in frontal cortical surface area during early adolescence. This stands in sharp contrast to the regional expansion observed in children with low genetic risk.
The study, utilizing data from over 6,000 participants, provides some of the earliest evidence that genetic liability for schizophrenia manifests as dynamic, diverging brain changes long before the typical onset of symptoms in young adulthood.
Key Research Findings
- A Critical Window: Early adolescence (ages 9 to 14) is identified as a vital developmental period where genetic risks begin to reshape the brain’s physical structure.
- Surface Area vs. Thickness: The study focused specifically on cortical surface area, which is genetically distinct from cortical thickness and may serve as a more sensitive marker for genetically driven neurodevelopmental processes.
- Specific Brain Regions: Children with high genetic risk showed surface area decreases in the caudal middle and superior frontal regions, areas where low-risk children showed expected growth.
- Unique to Schizophrenia: While genetic risks for ADHD and educational attainment were associated with “static” (persistently small or large) surface areas, only schizophrenia risk was linked to a dynamic change or “divergence” over time.
- Neurodevelopmental Origins: These findings support the theory that schizophrenia is rooted in early development, appearing as observable deviations in brain trajectories nearly a decade before formal diagnosis.
Source: Elsevier
Research has found that children with higher genetic susceptibility to schizophrenia show decreases in frontal cortical surface area during early adolescence, in contrast to the regional expansion observed in children with low genetic susceptibility.
This suggests that individuals with high genetic liability for schizophrenia may already show deviations in their neurodevelopmental trajectories before symptoms typically appear in young adulthood.
The findings from the new study in Biological Psychiatry, published by Elsevier, provide critical insights for refining developmental models of schizophrenia and for informing the timing of preventive interventions.
Over 60% of psychiatric disorders, including schizophrenia, manifest before age 25, with many exhibiting symptoms prior to a formal diagnosis. Early signs of psychopathology often emerge gradually during development.
Early adolescence is a critical window when there is both a heightened risk for emergent mental health problems and when the brain undergoes profound structural and functional changes.
“We know that certain psychiatric disorders are highly heritable with complex underlying genomic signatures. However, neuroimaging markers of mental illness remain elusive,” notes lead investigator Henning Tiemeier, MA, MD, PhD, Department of Social and Behavioral Sciences, Harvard T. Chan School of Public Health, Boston, MA, USA.
“Pinpointing the timing of when genetic risks begin to manifest in the brain could offer crucial clues for early diagnosis and intervention.”
The majority of studies to date have largely been cross-sectional, using data from a single snapshot in time. This longitudinal analysis used data from 6,228 participants aged 9 to 14 of European descent from the Adolescent Brain Cognitive Development (ABCD) Study and the Generation R Study.
With a total of 9,720 brain images collected from multiple MRI scans over the years, combined with genetic information, the study mapped out brain areas linked to polygenic liability and determined how these associations evolve over time as the children developed.
Children with low genetic susceptibility to schizophrenia showed expected increases in cortical surface area of the caudal middle and superior frontal regions during early adolescence, whereas those with higher genetic susceptibility showed decreases in these regions.
These findings provide evidence supporting the neurodevelopmental origins of schizophrenia; the impact of schizophrenia genetics on the brain can already be detected in early adolescence, long before the typical disease onset age.
“Our findings focused on cortical surface area rather than cortical thickness. This distinction is important because prior studies demonstrate that surface area and thickness are largely genetically separable phenotypes and follow distinct developmental trajectories, with surface area often showing stronger heritability and a different set of associated loci than thickness,” explains co-lead investigator Ryan Muetzel, PhD, Department of Child and Adolescent Psychology and Psychiatry, Erasmus University Medical Center Rotterdam, The Netherlands.
“Together, these findings indicate that surface area may be a particularly sensitive marker of genetically driven neurodevelopmental processes relevant to psychiatric disorders,” adds first author Bing Xu, MSc, Department of Child and Adolescent Psychology and Psychiatry, Erasmus University Medical Center Rotterdam, The Netherlands.
The study also examined genetic liability for other traits, including ADHD, autism, major depression, and educational attainment. While higher genetic scores for educational attainment and ADHD were associated with persistently larger and smaller surface areas, respectively, no significant associations were found with dynamic brain changes during this developmental period, highlighting a pattern unique to schizophrenia.
Dr. Tiemeier remarks, “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 showed up so early, and in such a consistent way, was quite surprising.
“The sharp divergence we observed stood in marked contrast to the persistent cortical patterns associated with genetic liability for ADHD and educational attainment, highlighting that not all genetic risks shape the adolescent brain in the same way.”
This study moves beyond static, cross-sectional associations between genetic risk and brain structure to identify when genetic risk begins to shape neurodevelopmental trajectories, providing some of the earliest in vivo evidence that genetic risk for schizophrenia is reflected in dynamic changes in the brain during a critical developmental window.
While this work is a significant step in elucidating the etiology of schizophrenia, the investigators observe that due to the large-scale nature of this study, they were able to detect relatively small effect sizes. Thus, further research is needed for these results to be of prognostic value at the individual level.
John Krystal, MD, Editor of Biological Psychiatry, concludes, “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 the development of children’s and young adults’ social and cognitive functions. This work highlights the importance of genetic risk for schizophrenia on the timing of these developmental changes.”
Key Questions Answered:
A: No. While the study detected these patterns on a large scale, the “effect sizes” were relatively small. Currently, these findings are for understanding the disease’s origins rather than providing a definitive prognosis for an individual child.
A: This is a window where the brain undergoes its most profound structural and functional transformations. It is also when over 60% of psychiatric disorders begin to manifest, making it the ideal time to look for the earliest signs of divergence.
A: By pinpointing when these genetic risks start to change the brain, doctors can better inform the timing of preventive interventions. It moves psychiatry toward a “preventative” model rather than just treating symptoms once they appear.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and schizophrenia research news
Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Image: The image is credited to 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 manifestations of genetic vulnerabilities to psychopathology are crucial for understanding disease onset and informing early intervention. However, when genetic risks begin to manifest in the brain remains unclear.
Methods
We leveraged 2 large neurodevelopmental cohorts: the Adolescent Brain Cognitive Development (ABCD) Study in the United States and the Generation R (GenR) Study in the Netherlands. Repeated-measures brain imaging data were collected from 6228 individuals of European descent (mean baseline age 10 years), with an average follow-up of 2 (ABCD) to 4 (GenR) years.
Using whole-brain vertexwise linear mixed models, we investigated how polygenic scores (PGSs) for 4 psychiatric disorders (attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder, schizophrenia [SCZ], major depressive disorder) and educational attainment were associated with brain morphological trajectories.
Results
Children with low genetic susceptibility to SCZ showed expected increases in cortical surface area of the caudal middle and superior frontal regions during early adolescence, whereas those with higher genetic susceptibility showed decreases in these regions, suggesting divergent neurodevelopmental trajectories that may begin during this period. No significant associations were found between other psychiatric PGSs and brain structural changes over time.
However, higher PGSs for educational attainment were associated with persistently larger surface areas, while higher PGSs for ADHD were related to persistently smaller surface areas in frontal and temporal lobes across time.
Conclusions
We showed that the impact of genetic susceptibility to SCZ may begin to manifest in the brain during early adolescence, revealing dynamic neurodevelopmental changes that may serve as potential biomarkers for early detection of SCZ.
