Origins of schizophrenia linked to epigenetics of the placenta

Scientists have uncovered a possible link between the placenta — the organ that provides oxygen and nutrients to a developing fetus — and the origins of mental illness.

If confirmed true, this finding could enhance scientists' understanding of how certain psychiatric disorders start to take root before birth, or are made more likely by events in the womb.

According to the "neurodevelopmental hypothesis," first proposed in 1987 by neuroscientist Daniel Weinberger, schizophrenia originates during fetal brain development. The theory suggests that a combination of genetic risk factors and prenatal conditions shape early brain wiring, thus increasing the likelihood of schizophrenia and other mental health disorders later in life.

While widely accepted as feasible, the exact mechanism behind this hypothesis is unclear.

Now, a recent study published March 14 in the journal Nature Communications, reveals that part of the answer may lie in epigenetic modifications in the placenta. These are chemical changes to DNA molecules that don't alter the genes within them, but rather affect which genes are switched on or off.

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In the study, scientists analyzed DNA from 368 placenta samples, focusing on a type of epigenetic change called DNA methylation, which affects gene expression. They identified more than 214,000 stretches of DNA in the placenta where DNA methylation often takes place.

Many of these methylated DNA sites were located in areas where DNA is actively used to produce RNA and proteins; RNA is a genetic cousin of DNA that helps shuttle blueprints out to protein construction sites in the cell. It's feasible, then, that DNA methylation can silence or activate genes involved in placental development and function, the team said. Changes in placental function are important because the placenta acts as an intermediate between the maternal environment and the fetus.

Past studies had already linked specific genes to psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. So the team compared their placenta DNA methylation data with existing data on these disorders, to see if the same genes cropped up.

They found that several psychiatric disorder-related genes are highly methylated in the placenta. Therefore, they hypothesized that methylation can affect the activity of these placental genes — changing whether or not they make proteins — which in turn would affect fetal brain development.

To explore these potential effects on the developing fetal brain, the researchers looked at how DNA methylation alters gene expression in the placenta. They found that many of the genes affected by DNA methylation are involved in immune responses. Based on these findings, they hypothesized that DNA methylation in the placenta influences the expression of immune-related genes, potentially raising the risk of infection in some cases.

Earlier studies have linked infections during pregnancy — including seasonal influenza and Zika — to altered neurodevelopment of the fetus and a higher risk of psychiatric disorders in offspring. Researchers believe that infections during pregnancy can interfere with fetal brain development by triggering maternal immune responses that then cause fetal brain inflammation; or, alternatively, germs may directly infect fetal brain cells.

The new research hints at a possible throughline between the epigenetics of the placenta and these harmful immune responses. However, "the one problem is that this paper does not provide direct experimental evidence that specific methylation patterns lead to schizophrenia or other neuropsychiatric disorders," John Loike, a professor of biology and bioethics at Touro University in New York, told Live Science in an email.

Instead of pinpointing those exact mechanisms, this study looks at changes in the placenta's DNA as a kind of marker to explore how conditions during pregnancy might be linked to brain disorders later in life, said Loike, who was not involved in the study. "Further research is necessary to substantiate these findings."

If this epigenetic link is confirmed, the finding could theoretically point to ways of preventing psychiatric disorders, the authors suggest.

"If we could identify risk factors at the prenatal stage, we could intervene before symptoms appear, adjusting treatments or designing personalized preventive strategies," Ariadna Cilleros-Portet, the first author of the study and a postdoctoral researcher at Mount Sinai Hospital in New York, said in a statement.