DNA Methylation Pattens in Newborns Point to Susceptibility to Schizophrenia

Genetic susceptibility to neurodevelopmental conditions such as schizophrenia, autism, and ADHD can be linked, in part, to distinct epigenetic signatures in newborn cord blood. An analysis of nearly 6,000 newborns in Biological Psychiatry, published by Elsevier, revealed that genetic susceptibility to neurodevelopmental conditions is already associated with measurable differences in DNA methylation (DNAm) patterns at birth. These differences were particularly strong for susceptibility to schizophrenia and clustered in genes involved in immune function, notably, the major histocompatibility complex, which has been consistently linked to schizophrenia risk and immune function in research on adults.

Neurodevelopmental conditions are strongly influenced by genetics and begin to take shape in the brain as early as in the womb. Yet, the biological mechanisms driving these early changes remain largely unknown. Researchers of the current study investigated DNAm, a chemical tag that can switch genes on or off without altering the underlying DNA sequence, as a potential biological pathway. DNAm helps the body regulate gene activity in response to both our genetic makeup and the environment in which we live.

“We examined whether genetic susceptibility to neurodevelopmental conditions is already linked to differences in DNAm patterns at birth, long before symptoms typically emerge. We analyzed cord blood DNAm from nearly 6,000 newborns across four European birth cohorts in the general population to capture the full spectrum of genetic risk,“ says co-lead investigator Charlotte A.M. Cecil, PhD, Erasmus MC University Medical Center Rotterdam, the Netherlands.

Investigators calculated polygenic scores for autism, ADHD, and schizophrenia and tested how these relate to neonatal DNAm. Newborns with higher genetic susceptibility to schizophrenia showed differences in DNAm patterns at hundreds of sites across the genome, especially in immune-related regions. Signal for ADHD and autism was more subtle, meaning broader genomic regions were involved with consistent but less strong effects.

John Krystal, MD, Editor of Biological Psychiatry, comments, “This study reveals that the increased risk for disorders like schizophrenia can be detected by sampling blood at the earliest possible stage—at birth. Early detection of genetic susceptibility and risk could become a critical component of primary and secondary preventive efforts for neurodevelopmental disorders, years before symptom onset.”

Investigators were surprised to observe such a strong epigenetic signal for schizophrenia, which usually manifests much later than other neurodevelopmental disorders—in late adolescence and young adulthood—and is less prevalent in the general population.

“Schizophrenia showed the clearest neonatal DNAm pattern, particularly in immune-related genomic regions known to be implicated in this condition, which was an intriguing and informative result. This is an important piece of evidence supporting schizophrenia’s fetal origin—a perspective that is currently under debate. That does not mean a diagnosis is predetermined, but it does mean we can start asking better questions about when and how susceptibility is embedded,” points out co-lead investigator Isabel K. Schuurmans, PhD, Erasmus MC University Medical Center Rotterdam, the Netherlands.

In the long term, integrating epigenetic data with genetic information may help refine early risk stratification or screening research, but clinical application will require replication, the inclusion of diverse populations, and careful evaluation, as only a fraction of children in the general population will eventually develop these conditions.

Dr. Cecil concludes, “Finding immune-related epigenetic signatures at birth highlights promising pathways to investigate. Our goal is to use these insights to better understand how and when neurodevelopmental risk occurs in order to ultimately inform prevention and timely support.”

Notes for editors

The article is "Genetic Susceptibility to Neurodevelopmental Conditions Associates With Neonatal DNA Methylation Patterns in the General Population: An Individual Participant Data Meta-Analysis,” by Isabel K. Schuurmans, Dinka Smajlagic, Vilte Baltramonaityte, Anni L.K. Malmberg, Alexander Neumann, Nicole Creasey, Janine F. Felix, Henning Tiemeier, Jean-Baptiste Pingault, Darina Czamara, Katri Raïkkönen, Chistian Magnus Page, Robert Lyle, Alexandra Havdahl, Jari Lahti, Esther Walton, Mona Bekkhus, and Charlotte A.M. Cecil (https://doi.org/10.1016/j.biopsych.2025.09.005). It appears online in Biological Psychiatry, published by Elsevier.

The article is openly available at https://www.biologicalpsychiatryjournal.com/article/S0006-3223(25)01463-5/fulltext.

Copies of the full text and additional information are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]. Journalists wishing to interview the authors should contact Isabel K. Schuurmans, PhD, at [email protected], or Charlotte A.M. Cecil, PhD, at [email protected].

The authors’ affiliations and disclosures of financial and conflicts of interests 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 and conflicts of interests are available here.

This work was supported by the European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529; HappyMums, grant agreement No 101057390) and the European Research Council (TEMPO; grant agreement No 101039672).

About Biological Psychiatry

Biological Psychiatry is the official journal of the Society of Biological Psychiatry, 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.

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