Summary: In a paradigm shift, researchers found over 100 genes associated with schizophrenia risk operate primarily through their role in the placenta, rather than the developing brain.
The research emphasizes the placenta’s significance in illness development, challenging the century-old assumption that genes for schizophrenia risk primarily affect the brain.
The study also discovered that these risk genes influence the placenta’s critical function of sensing and exchanging nutrients with the mother’s bloodstream. The findings suggest that assessing placenta health could be key to early intervention and prevention of developmental disorders.
The study found that over 100 genes linked to schizophrenia risk function mainly through their role in the placenta, not the brain, challenging a long-held assumption in the field.
These schizophrenia risk genes significantly impact the placenta’s ability to sense and exchange nutrients from the mother’s bloodstream, affecting the health of the developing fetus.
The researchers identified genes in the placenta associated with other disorders such as diabetes, bipolar disorder, depression, autism, and ADHD, and found that schizophrenia has more genetic associations than any of these other conditions.
Source: Lieber Institute for Brain Development
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 a new study led by the Lieber Institute for Brain Development.
Scientists had generally assumed for over a century that genes for schizophrenia risk were principally, if not exclusively, about the brain.
But the latest research, just published in Nature Communications, found that the placenta plays a much more significant role in developing illness than previously known.
“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,” says Daniel Weinberger, M.D., senior author of the paper and Director and CEO of the Lieber Institute for Brain Development, located on the Johns Hopkins medical campus in Baltimore.
“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 researchers 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-fetal nutrient exchange, called trophoblasts, negatively affecting the placenta’s role in nurturing the developing fetus.
The paper also identifies several genes in the placenta that are causative factors for diabetes, bipolar disorder, depression, autism and attention deficit hyperactivity disorder, or ADHD.
The scientists, however, found far more genetic associations with genes for schizophrenia than for any of these other disorders.
The researchers 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.
“Targeting placenta biology is a crucial new potential approach to prevention, which is the holy grail of public health,” says Gianluca Ursini, M.D., Ph.D., the lead author on the paper and an investigator at the Lieber Institute.
“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 scientists 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 seem to play a central role.
Previous research has shown males are more vulnerable than females to prenatal stress. Generally speaking, developmental disorders such as schizophrenia occur more frequently in men and boys.
The researchers also uncovered concerning results about COVID-19 pregnancies. The scientists 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 because of how infection affects the placenta. Lieber Institute scientists are pursuing this possibility with NIH-funded research examining COVID-19 placentas to learn more.
The Lieber Institute researchers hope their ongoing study of the genes of the placenta will one day lead to new treatment and diagnostic tools, perhaps revolutionizing the field of prenatal medicine.
“In the modern era of molecular and genetic medicine, the standard treatment for a complicated pregnancy is still primarily bedrest,” says Dr. Weinberger. “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.”
About this schizophrenia and genetics research news
Prioritization of potential causative genes for schizophrenia in placenta
Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories.
Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes.
We performed TWAS in healthy term placentae (N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain (N = 166) and additional placenta TWAS for other disorders/traits.
The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness.
These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies.
Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone.