The placenta may play a role in the genetic risk of schizophrenia

Johns Hopkins researchers have found genes associated with an important placental function tied to schizophrenia risk.

Researchers have found evidence that the genetic risk of schizophrenia may play out not only in the brain, but in another especially crucial place: the placenta.

Over 100 genes linked to increased risk of schizophrenia appear to cause illness through the roles they play in the placenta, rather than in brain development directly, according to a team at Johns Hopkins’ Lieber Institute for Brain Development (LIBD) and the Icahn School of Medicine.

Their study, published in Nature Communications, suggests that an assumption held for over a hundred years that the genetic risk of schizophrenia was primarily, or even totally, centered on the brain may be incorrect. 

Over 100 genes linked to increased risk of schizophrenia appear to cause illness through the roles they play in the placenta, rather than in brain development directly.

These other pathways for the genetic risk of schizophrenia have been “hiding in plain sight,” Daniel Weinberger, senior author and director and CEO of the LIBD, said

“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.”

A crucial development: The placenta is a necessity for nearly all mammalian births (looking at you, monotremes and marsupials!). During pregnancy, this ad hoc organ forms to connect the developing baby to the uterus. Along with the umbilical cord, it acts as the baby’s “lifeline,” providing oxygen and nutrients while removing CO2 and waste, producing hormones needed for growth, and imparting starter antibodies. 

It is essentially kidney, liver, and lungs in one, and when the baby is born, the placenta (generally) leaves with it. It is essential for human development, and according to this study, it may also play a larger role in the risk of developing schizophrenia than previously understood.

The genetic risk of schizophrenia: Schizophrenia is a very complex, widely misunderstood, and popularly demonized mental health disorder, characterized by delusions, hallucinations, and erratic or unusual behavior which impacts patients’ day-to-day life.

Schizophrenia is estimated to affect 1% of the world’s population, and men are more likely to develop it, with onset generally occurring late in childhood or in early adulthood. It is also significantly heritable, the researchers note, with a heritability of about 50-80%.

Studies have so far found hundreds of gene locations that are associated with a genetic risk of schizophrenia, the researchers write — with most variants having only a tiny effect on the outcome, in total explaining about 7% of the risk — leaving much still unexplained.

The team found that many genes associated with schizophrenia influenced an important part of the placenta’s job.

Placental risk: For their study, the team looked at over 100 placenta samples using a technique called a “transcriptome-wide association study.”

What the team found, through this and other assays, was that many genes associated with schizophrenia influenced an important part of the placenta’s job. Specifically, they altered the placenta’s ability to sense important nutrients in the mother’s bloodstream — including oxygen — and adjust what it delivers and takes away accordingly.

This makes the placenta less effective and negatively impacts the developing fetus.

The team found that the baby’s sex may also play a role in how schizophrenia-related genes impact the placenta. In samples from pregnancies of male babies, inflammation seemed to play a bigger role; prior research has found male babies to be more vulnerable to prenatal stress, and schizophrenia does tend to occur more often in men.

Beyond schizophrenia, understanding how the placenta may play a role in developing illnesses and disorders could become an important medical approach.

A new approach: The study may be a promising new lead in explaining the mysterious causes of schizophrenia. More broadly, understanding how the placenta may play a role in developing illnesses and disorders could become an important medical approach, the authors suggest.

“Targeting placenta biology is a crucial new potential approach to prevention, which is the holy grail of public health,” lead author Gianluca Ursini, an investigator at LIBD, said.

“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.”

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