Schizophrenia is one complex disease, with a number of subtypes and an origin unknown. However, despite it’s complexity, recent evidence points toward an interaction between genes and environment that are mediated by the epigenome. Further adding to the complexity is the fact that most patients are treated with powerful antipsychotics that also remodel the epigenome in a number of tissues, including the brain.

But a carefully designed EWAS can reveal a lot about the altered DNA methylation in the brain, and the Lab of Jonathan Mill at University of Exeter Medical School and King’s College London, which brought us a recent and beautifully informative Alzheimer’s EWAS, is now tackling the developmental origins of schizophrenia by comparing adult brains to developing brains in order to remove some of the confounding variables of life’s course.

Here’s what the team found by profiling matched prefrontal cortex and cerebellum tissue in schizophrenics and matched controls:

Disease associated differentially methylated regions (DMRs) at numerous loci, with a strong bias for the prefrontal cortex, and a nice replication in independent brain samples.

There are “discrete modules of co-methylated loci” associated with schizophrenia.

The modules are involved in neurodevelopment and have been implicated in a number of other GWAS studies on schizophrenia.

Putting the icing on the cake, the team then looked at fetal cortex samples and found that the DMRs they identified are significantly enriched for loci that undergo dynamic DNA methylation remodeling during neurodevelopment.

Senior Author Jonathan Mill shares that “The regions we identified as differentially methylated in frontal cortex tissue from patients overlapped considerably with areas of the genome that show dynamic changes during brain development. This is really interesting given the strong evidence for the neurodevelopmental origins of schizophrenia. We also identified modules of co-methylated loci associated with schizophrenia. The genes in these modules contained a number that have been strongly implicated in the disease from recent genetic studies – e.g. the recent Psychiatric Genetics Consortium’s GWAS analysis.”

First author Ruth Pidsley concludes that “By using precious post-mortem brain samples we were able to pinpoint schizophrenia associated DNA methylation changes in disease relevant tissue. Our results reaffirm the importance of the frontal cortex in the disorder, and lend support to the neurodevelopmental model of schizophrenia”.

Learn more about how great experimental design can unravel the complexities of neurodevelopment in Genome Biology, October 2014