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Schizophrenia Associated With Blood DNA Methylation Signature

NEW YORK – A new epigenetic study suggests cytosine methylation marks found in the blood can provide a window into schizophrenia risk and schizophrenia-related shifts in brain connectivity. 

"[W]e identified a blood DNA methylation signature that reproducibly differentiated schizophrenia from [healthy controls] and several other major neuropsychiatric disorders," senior author Emanuel Schwarz, a researcher at the Central Institute of Mental Health in Mannheim, Germany, and his colleagues wrote in a JAMA Psychiatry paper published Wednesday, noting that the findings "help to characterize the systems-level association between genetic, epigenetic, and environmental risk for schizophrenia."

As part of an international case-control study done over a decade, Schwarz and colleagues analyzed whole blood DNA methylation profiles for 803 individuals with schizophrenia and more than 100 individuals with conditions such as autism spectrum disorder (ASD), bipolar disorder (BD), or major depressive disorder (MDD), along with 1,238 healthy controls and dozens of first-degree relatives of patients.

Through a series of discovery and validation analyses, the team tracked down a set of methylation marks that coincided with schizophrenia, including cytosine methylation marks in or around genes from brain synapse- and neurodevelopment-related pathways. For a subset of the cases and controls, the group brought in magnetic resonance imaging (MRI) data to search for ties to altered connections in the dorsolateral prefrontal cortex hippocampus (DLPFC-HC) brain region.

"One of the best established intermediate phenotypes of schizophrenia is [DLPFC-HC] connectivity during [working memory] performance," the authors explained, noting that changes in DLPFC-HC connectivity have also turned up in first-degree family members of schizophrenia patients and in individuals carrying schizophrenia-associated genetic variants.

Using a machine learning method and clues from available genetic risk data, the investigators subsequently came up with a schizophrenia-related polymethylation score that appeared to track with the schizophrenia-related methylation and connectivity changes found in postmortem brain in an analysis of DLFC brain samples from 108 individuals with schizophrenia and 136 healthy controls.

Moreover, in healthy controls who had methylation patterns that were closer-than-usual to the schizophrenia signature, the team saw brain connectivity changes in the DLPFC-HC by MRI.

"We identified a reproducible blood DNA methylation signature specific for schizophrenia that was correlated with altered functional DLPFC-HC coupling during working memory, and mapped to methylation differences found in DLPFC postmortem samples," the authors reported.

The work "indicates a possible epigenetic contribution to a schizophrenia intermediate phenotype," the authors reported, "and suggests that [a schizophrenia polymethylation score] could be of interest to be studied in the context of multimodal biomarkers for disease stratification and treatment personalization."