Schizophrenia Tied to Epigenetic Changes Before Birth

Megan Brooks

December 04, 2015

The theory that schizophrenia has its origins in early brain development got a boost from two studies published online November 30 in Nature Neuroscience.

Both studies focus on DNA methylation, an epigenetic process that modifies the function of DNA and that appears to be important in brain development and, potentially, in schizophrenia.

In one study, researchers combined high-density DNA methylation profiling with genome-wide single-nucleotide polymorphism genotyping in 166 human fetal brain samples from the first and second trimesters of gestation.

"Our data show that there are considerable genetic effects on DNA methylation in the developing human brain," Jonathan Mill, PhD, professor of epigenetics, University of Exeter Medical School, and head of the psychiatric epigenetics group, King's College London, who led the study, told Medscape Medical News.

These are termed fetal brain methylation quantitative trait loci (mQTLs), he explained. Most of these effects occur locally (in cis), but some genetic influences occur over long distances (in trans), even between chromosomes.

"These effects appear to be enriched within genomic regions associated with schizophrenia. This is interesting, given the hypothesized neurodevelopment origins of schizophrenia, and suggests that disease-associated genetic variants influence gene regulation during key periods of brain development," Prof Mill said.

"Understanding the genetic effects of risk variants on gene regulation during the earliest stages of brain development may point us towards the underlying biology of schizophrenia,” first author Eilis Hannon, PhD, of the University of Exeter Medical School, added in a statement.

DNA mQTLs can be used to refine genome-wide association study loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk varients, the authors note in their article.

Prof Mill told Medscape Medical News that their findings "align well" with those in the companion article in Nature Neuroscience, which also implicate epigenetic changes in the prenatal period in risk for schizophrenia.

"Far-reaching" Implications

In that second study, Andrew Jaffe, PhD, from the Lieber Institute for Brain Development, Baltimore, Maryland, and colleagues mapped DNA methylation across development in postmortem prefrontal cortex brain tissue from 191 individuals who had schizophrenia and 335 individuals who had no history of psychiatric disorder, who served as controls.

They identified "widespread" DNA methylation changes in the transition from prenatal to postnatal life. "Notably, these developmentally associated changes in DNA methylation were significantly enriched for genomic regions that confer clinical risk for schizophrenia," they report.

The researchers identified 2104 individual citosine–phosphate–guanine sites (CpGs) that differed between schizophrenia patients and control individuals that were enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs "strongly correlate with changes related to the prenatal-postnatal transition."

"The differences found between patients and controls appear to represent epigenetic marks that principally associate with early neurodevelopment and not with events that herald the onset of the disorder or that characterize adult brain biology. Overall, the data suggest that both the genetic and environmental risk components of schizophrenia involve early developmental influences," Dr Jaffe and colleagues conclude.

In a statement, Daniel R. Weinberger, MD, director and CEO of the Lieber Institute for Brain Development, said these results have "potentially far-reaching implications for how we understand schizophrenia, how we develop experimental models of this illness in scientific laboratories, how we search for new ways to prevent the disorder from happening, and how we treat it once it does."

Neither study had commercial funding. The authors have disclosed no relevant financial relationships.

Nature Neurosci. Published online November 30, 2015. Hannon et al, abstract; Jaffe et al, abstract

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