The new findings, published in the journal Nature Medicine, reveal that schizophrenia genes appear to be “turned on” during complicated pregnancies, and the more these genes are turned on, the more the placenta shows other signs of stress such as inflammation.
This new discovery would allow scientists to more accurately predict mental illness and to develop strategies to prevent or reduce its occurrence by improving the health and resiliency of the placenta.
“For the first time, we have found an explanation for the connection between early life complications, genetic risk, and their impact on mental illness, and it all converges on the placenta,” said Dr. Daniel R. Weinberger, who led the team of investigators on the study and is CEO of the Lieber Institute for Brain Development (LIBD) in Baltimore, Md.
In contrast to previous research that focused on how genes tied to behavioral disorders directly alter prenatal brain development, the new study found that many genes associated with risk for schizophrenia appear to alter early brain development indirectly, by affecting the health of the placenta.
The placenta has been the subject of myth and ritual in many cultures, and yet it remains a widely neglected human organ in science, despite its essential role in supplying critical nutrients and chemicals for normal prenatal development. In fact, the placenta is the only organ removed from the body that is not routinely sent to the laboratory for examination.
For more than two decades, brain development during pregnancy and shortly after birth has remained central to a hypothesis that schizophrenia is a neurodevelopment disorder. But the biological mechanisms involved were poorly understood.
Prior research has found that genetic variants alone increase the odds of developing schizophrenia by only a fraction, while early life complications during pregnancy and labor can increase risk up to twofold.
For the new study, the researchers analyzed over 2,800 adult individuals, 2,038 of whom had schizophrenia, of various ethnic backgrounds from four countries, including the U.S., Europe and Asia. All had undergone genetic testing and were surveyed for obstetrical history information.
Researchers found a significant link between genes associated with risk for schizophrenia and a history of a potentially serious pregnancy complication. People with a high genetic risk and serious early life complications have at least a fivefold greater likelihood of developing schizophrenia compared to those with similarly high genetic risk but no history of serious obstetrical complications.
This information led to a series of analyses of gene expression in several placenta tissue samples, including samples of placenta from complicated pregnancies that include preeclampsia and intrauterine growth restriction. The findings reveal a striking and consistent turning on of the schizophrenia genes in these placentae.
One of the many mysteries of such developmental behavioral disorders is why their incidence is two to four times greater in males than in females.
The new findings may shed light on this mystery. They show that the schizophrenia genes turned on in the placenta from complicated pregnancies were significantly more common in placentas from male compared with female children. The placenta appears to be at least part of the explanation for the sex bias associated with these disorders.
“The surprising results of this study make the placenta the centerpiece of a new realm of biological investigation related to how genes and the environment interact to alter the trajectory of human brain development,” said Weinberger.