Summary: New longitudinal research shows that children with higher genetic susceptibility to schizophrenia display a measurable reduction in frontal cortical surface area during early adolescence (roughly ages 9–14). In contrast, children with low genetic risk exhibit the expected regional expansion during the same developmental window. These patterns emerge from MRI data and genetic profiles collected well before the typical age of schizophrenia onset, offering early in vivo evidence that genetic liability can alter brain developmental trajectories.
The analysis pooled repeated brain imaging and genetic data from large, well-characterized cohorts to track how polygenic risk for schizophrenia and other traits relate to changing brain structure across early adolescence. Results highlight a specific, dynamic divergence in cortical surface area for schizophrenia risk that is distinct from the more static associations observed for other traits such as ADHD and educational attainment.
Key Research Findings
- A Critical Developmental Window: Early adolescence (approximately ages 9–14) is identified as a period when genetic liability for schizophrenia begins to influence measurable brain changes.
- Surface Area vs. Thickness: The study emphasizes cortical surface area as a genetically separable and developmentally distinct phenotype from cortical thickness. Surface area may offer greater sensitivity to genetically driven neurodevelopmental processes relevant to psychiatric risk.
- Regional Specificity: Children with higher genetic risk for schizophrenia showed decreases in surface area in the caudal middle and superior frontal regions, whereas low-risk peers showed the typical increases in these regions during early adolescence.
- Schizophrenia-Specific Dynamics: Genetic liability for schizophrenia was uniquely associated with dynamic changes over time (diverging trajectories). In contrast, higher genetic scores for educational attainment and ADHD related to persistently larger or smaller surface areas, respectively, rather than to changing trajectories.
- Supports Neurodevelopmental Origin: These findings are consistent with models that position schizophrenia as rooted in early brain development, with genetic influences detectable years before clinical onset.
Source: Elsevier
This study, published in Biological Psychiatry, examined how polygenic scores (PGSs) for several psychiatric disorders and for educational attainment relate to brain morphology trajectories across early adolescence. Using repeated MRI assessments and genetic data, the investigators mapped where and when genetic risk affects cortical development.
Over 6,200 participants of European descent were included (n = 6,228), with a mean baseline age around 10 years. The combined dataset comprised 9,720 MRI scans gathered across follow-up visits from the Adolescent Brain Cognitive Development (ABCD) Study and the Generation R Study. Whole-brain vertexwise linear mixed models were used to assess how PGSs for schizophrenia, ADHD, autism spectrum disorder, major depressive disorder, and educational attainment related to changes in cortical surface area and thickness over time.
Key patterns emerged: children with low genetic susceptibility to schizophrenia showed the expected developmental increases in surface area in specific frontal regions, while those with higher schizophrenia PGSs showed decreases in the same areas during early adolescence. Other psychiatric PGSs did not show similar dynamic associations; instead, higher PGSs for educational attainment were associated with persistently larger surface areas, and higher PGSs for ADHD were associated with persistently smaller surface areas across frontal and temporal regions.
Lead investigator Henning Tiemeier, MA, MD, PhD, explains that identifying when
First author Bing Xu, MSc, notes that the observed divergence for schizophrenia was pronounced and consistent across the sample, distinguishing it from the static patterns linked to ADHD and educational attainment. The authors stress that while these group-level effects are detectable in large samples, effect sizes are relatively small, so the findings currently inform models of disease origin rather than individual-level prognosis.
John Krystal, MD, Editor of Biological Psychiatry, comments that altered brain structure and function emerging during development are central to understanding schizophrenia. Early neurodevelopmental divergence may have downstream implications for cognitive and social functioning in adolescence and young adulthood, and these results underscore the value of examining timing as well as location of brain changes associated with genetic risk.
Key Questions Answered:
A: No. The study detected group-level patterns with relatively small effect sizes. These results improve understanding of disease origins and timing but are not diagnostic or predictive at the individual level.
A: Early adolescence is a phase of pronounced structural and functional brain remodeling and coincides with the period when many psychiatric disorders first begin to appear, making it an optimal window to detect early divergence linked to genetic risk.
A: By revealing when genetic risk starts to alter brain development, clinicians and researchers can better consider timing for preventive or early-intervention approaches, shifting psychiatry toward earlier, potentially preemptive strategies rather than waiting to treat symptoms after they emerge.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by editorial 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
Understanding when genetic vulnerabilities manifest in the developing brain is essential for clarifying disease onset and for designing timely interventions. Prior work has been limited by cross-sectional designs and has often focused on static measures rather than trajectories.
Methods
This study combined repeated neuroimaging from two large cohorts—the ABCD Study (United States) and the Generation R Study (Netherlands)—including 6,228 participants of European ancestry (mean baseline age around 10). Participants contributed a total of 9,720 MRI scans with follow-up ranging from approximately 2 to 4 years. Vertexwise linear mixed models were used to test associations between polygenic scores for psychiatric disorders and educational attainment and longitudinal changes in cortical surface area and thickness.
Results
Children with low genetic susceptibility to schizophrenia exhibited expected increases in surface area of caudal middle and superior frontal regions during early adolescence, whereas children with higher schizophrenia polygenic scores showed decreases in these same regions, indicating divergent developmental trajectories beginning in this period. Other psychiatric polygenic scores did not show comparable dynamic associations. Instead, higher polygenic scores for educational attainment corresponded to persistently larger surface areas, and higher polygenic scores for ADHD corresponded to persistently smaller surface areas across frontal and temporal lobes.
Conclusions
The findings indicate that genetic susceptibility to schizophrenia can shape brain development during early adolescence, producing dynamic changes in cortical surface area that may serve as early biomarkers. While effect sizes are modest, these results refine developmental models of schizophrenia and point to critical timing for future research on early detection and prevention.