Researchers may have identified a reproducible blood DNA-methylation signature specific to schizophrenia, which is linked to altered dorsolateral prefrontal cortex hippocampal (DLPFC-HC) functional connectivity and methylation differences. The findings point to a potential epigenetic basis for schizophrenia, according to study results published in JAMA Psychiatry.

Working memory is impaired in schizophrenia, and epigenetic mechanisms such as DNA methylation may contribute to illness risk. Moreover, this mechanism may be an explanation for heritability not captured by other methods such as polygenic risk scores (PRSs). Consequently, the researchers explored whether a blood marker of epigenetic risk for schizophrenia, quantified as polymethylation score (PMS), can differentiate schizophrenia from health controls and predict brain function.

In this international case-control study, researchers examined genome-wide DNA methylation data from 2230 whole blood samples and 6 independent cohorts to determine whether PMS was associated with DLPFC-HC connectivity and potential interactions with a schizophrenia PRS. The sample comprised patients with schizophrenia (n=803), bipolar disorder (n=39), major depressive disorder (n=35), and autism (n=27), as well as healthy controls (n= 1238) and first-degree relatives of all patient groups (n=88). The study also looked at genome-wide DNA methylation data from postmortem DLPFC samples (136 healthy donors and 108 donors with schizophrenia) to assess whether peripheral PMS was mirrored by analogous changes in the brain.

Across 3 independent data sets, PMS signature was associated with schizophrenia (area under the curve [AUC] from 0.69 to 0.78; P value from 0.049 to 1.24×10−7) and data from postmortem DLPFC samples (AUC, 0.63; P =1.42×10−4) but not with major depressive disorder, autism, or bipolar disorder. Healthy controls with PMS similar to the schizophrenia cohort showed significantly altered DLPFC-HC connectivity, mirroring the lack of functional decoupling in schizophrenia. No significant association was discovered concerning the interaction between PMS and PRS with DLPFC-HC connectivity (P >.19).


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The pathways that distinguished schizophrenia from other profiles were primarily related to synaptic and neurodevelopmental processes. However, study limitations included potential complications introduced by patients taking medications, which could influence PMS. In addition, the explained variance in the brain data was comparatively low from postmortem DLPFC samples.

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The researchers concluded, “These results help to characterize the systems-level association between genetic, epigenetic, and environmental risk for schizophrenia.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Chen J, Zang Z, Braun U, et al. Association of a reproducible epigenetic risk profile for schizophrenia with brain methylation and function [published online February 12, 2020]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.4792