Genetic Risk of Schizophrenia Manifests in Early Adolescence, Study Shows

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 studyopens in new tab/window in Biological Psychiatryopens in new tab/window, 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.”

Notes for editors

The article is "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 (https://doi-org.ucc.idm.oclc.org/10.1016/j.biopsych.2026.03.989opens in new tab/window). It is published online in Biological Psychiatry, published by Elsevier.

The article is openly available at https://www.biologicalpsychiatryjournal.com/article/S0006-3223(26)01104-2/fulltextopens in new tab/window.

Full text of the study and additional information are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]opens in new tab/window. Journalists wishing to interview the authors should contact Ryan Muetzel, PhD, at [email protected]opens in new tab/window.

This work is supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200) and the Academy Ter Meulen Grant of the Academy Medical Sciences Fund of the Royal Netherlands Academy of Arts and Sciences (KNAW) (KNAWWF/1085/TMB23428).

The authors’ affiliations and disclosures of financial relationships and conflicts of interest are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial relationships and conflicts of interest are available hereopens in new tab/window.

About Biological Psychiatry

Biological Psychiatryopens in new tab/window is the official journal of the Society of Biological Psychiatryopens in new tab/window, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms, and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 9^th out of 156 Psychiatry titles and 17^th out of 271 Neurosciences titles in Journal Citation Reports^TM, published by Clarivate. The 2024 Impact Factor score for Biological Psychiatry is 9.0.www.sobp.org/journalopens in new tab/window

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