Epigenetic profile of the immune system associated with symptom severity and treatment response in schizophrenia.

Abstract

Environmental modification of genetic information (epigenetics) is often invoked to explain interindividual differences in the phenotype of schizophrenia. In clinical practice, such variability is most prominent in the symptom profile and the treatment response. Epigenetic regulation of immune function is of particular interest, given the therapeutic relevance of this mechanism in schizophrenia. We analyzed the DNA methylation data of immune-relevant genes in patients with schizophrenia whose disease duration was less than 3 years, with previous lifetime antipsychotic treatment of no more than 2 weeks total. A total of 441 patients met the inclusion criteria. Core symptoms were consistently associated with 206 methylation positions, many of which had previously been implicated in inflammatory responses. Of these, 24 methylation positions were located either in regulatory regions or near the CpG islands of 20 genes, including the SRC gene, which is a key player in glutamatergic signalling. These symptom-associated immune genes were enriched in neuronal development functions, such as neuronal migration and glutamatergic synapse. Compared with using only clinical information (including scores on the Positive and Negative Syndrome Scale), integrating methylation data into the model significantly improved the predictive ability (as indicated by area under the curve) for response to 8 weeks of antipsychotic treatment. We focused on a small number of methylation probes (immune-centred search) and lacked nutritional data and direct brain-based measures. Epigenetic modifications of the immune system are associated with symptom severity at onset and subsequent treatment response in schizophrenia.