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Placenta plays a central role in genetic schizophrenia risk



More than 100 genes linked to the risk of schizophrenia seem to cause illness because of their role in the placenta rather than in the developing brain, according to new research by the Lieber Institute for Brain Development.

For over a century, scientists had generally assume that genes for schizophrenia risk were principally, if not exclusively, about the brain.

But the new research found that the placenta plays a much more significant role in developing illness than previously known.

Daniel Weinberger, M.D., Director and CEO of the Lieber Institute for Brain Development, located on the Johns Hopkins medical campus in Baltimore, US, said:

“The secret of the genetics of schizophrenia has been hiding in plain sight—the placenta, the critical organ in supporting prenatal development, launches the developmental trajectory of risk.

“The commonly shared view on the causes of schizophrenia is that genetic and environmental risk factors play a role directly and only in the brain, but these latest results show that placenta health is also critical.”

The scientists found that schizophrenia genes influence a critical function of the placenta to sense nutrients in the mother’s bloodstream, including oxygen, and exchange nutrients based on what it finds.

The schizophrenia risk genes are more lowly expressed in the cells of the placenta that form the core of this maternal-foetal nutrient exchange, called trophoblasts, negatively affecting the placenta’s role in nurturing the developing foetus.

The paper also identified several genes in the placenta that are causative factors for diabetes, bipolar disorder, depression, autism and attention deficit hyperactivity disorder (ADHD).

The researchers, however, found far more genetic associations with genes for schizophrenia than for any of these other disorders.

They also discovered that the risk genes for schizophrenia found in the placenta may have a relatively greater effect on heritability, the likelihood of illness inherited from ancestors, than risk genes found in the brain.

Gianluca Ursini, M.D., Ph.D., the lead author on the paper and an investigator at the Lieber Institute, said:

“Targeting placenta biology is a crucial new potential approach to prevention, which is the holy grail of public health.

“Scientists could detect changes in placental risk genes decades before the possible onset of a disorder, possibly even in the mother’s bloodstream during pregnancy.

“If doctors knew which children were most at risk of developmental disorders, they could implement early interventions to keep them healthy.”

The researchers also found interesting sex-based differences in the placenta risk genes.

Different genes were associated with schizophrenia risk based on whether the placenta came from a male or female child.

In pregnancies with male children, inflammatory processes in the placenta appear to play a central role.

Previous research has shown that males are more vulnerable than females to prenatal stress.

Generally speaking, developmental disorders such as schizophrenia occur more frequently in men and boys.

The scientists also uncovered concerning results about COVID-19 pregnancies.

The researchers studied a small sample of placentas from mothers who had COVID-19 during pregnancy and found the schizophrenia genes for placenta risk were dramatically activated in these placentas.

The finding indicates that COVID-19 infection during pregnancy may be a risk factor for schizophrenia due to the way infection affects the placenta.

Lieber Institute researchers are pursuing this possibility with NIH-funded research examining COVID-19 placentas to learn more.

The Lieber Institute scientists hope their ongoing study of the genes of the placenta will one day lead to new treatment and diagnostic tools, perhaps revolutionising the field of prenatal medicine.

Dr Weinberger said:

“In the modern era of molecular and genetic medicine, the standard treatment for a complicated pregnancy is still primarily bedrest.

“These new molecular insights into how genes related to disorders of the brain and other organs play out in the placenta offer new opportunities for improving prenatal health and preventing complications later in life.”

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