Schizophrenia risk detectable at birth through epigenetic signatures

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."

Charlotte A.M. Cecil, PhD, co-lead investigator, 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."

Caption: A study in Biological Psychiatry has identified an epigenetic signature in newborns for genetic susceptibility to schizophrenia, revealing that an increased genetic risk of schizophrenia and other neurodevelopmental conditions can be detected at birth via cord blood sampling. (Credit: Biological Psychiatry / Schuurmans et al.)

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."