Placenta health tied to schizophrenia risk

By Marilynn Larkin

NEW YORK (Reuters Health) – Genes associated with risk of schizophrenia are "turned on" in a stressed placenta during complicated pregnancies, researchers have found.

"It's been known for decades that complicated births are risk factors for many developmental behavioral disorders, including autism, ADHD, (and) schizophrenia," Dr. Daniel Weinberger of the Lieber Institute for Brain Development, Johns Hopkins Medical Campus in Baltimore told Reuters Health. "We report the first insight into the biological underpinnings of these mysteries and the surprising culprit is the placenta."

"The placenta is the most neglected organ in the human body, the only organ removed from a human being that is not routinely sent to the laboratory for examination," he said by email. "Most often, it is thrown out!! These new research findings indicate that the placenta will become a centerpiece of biological research about human brain development."

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As reported online May 28 in Nature Medicine, Dr. Weinberger and colleagues analyzed data from 2,885 adults across the US, Italy, Germany, and Japan, including 2,038 with schizophrenia.

In a discovery sample of 234 patients with schizophrenia and 267 controls, all from the US, they explored the interaction between genomic risk for schizophrenia (genome-wide association study-derived polygenic risk score 1) and a history of early life complications (ELCs), such as pre-eclampsia, intrauterine growth restriction, and prematurity. They found that the association between genetic risk and schizophrenia was affected by ELC history.

"The combination of genetic risk and pregnancy complications increased the risk of illness more than five-fold," Dr. Weinberger said. "This is because these risk factors—genes and the prenatal environment—interact, and the effect is more than additive."

The team then grouped individuals in quintiles based on their PRS1 levels and determined odds ratios (ORs) of being affected by schizophrenia. They also stratified the samples by ELC history. They found that the OR increased with higher PRS1 quintiles only in the sample with ELCs. Having the highest PRS1 quintile corresponded to an OR of 8.36 in the presence of ELCs, but only 1.55 in the absence of ELCs, compared with those in the lowest PRS1 quintile.

"The more the placenta shows evidence of being under biological stress, as reflected in how inflamed it is, the more these genes associated with schizophrenia are turned on (ie, expressed)," Dr. Weinberger noted.

Further, he added, "All of these effects are greater if the placenta is from a male offspring than from a female offspring."

To replicate the findings, the team assessed additional case-control samples from Germany and Italy and found similar results.

Further investigations showed that the genes associated with schizophrenia that were affected by ELCs were highly expressed in the placenta and that their expression tended to be abnormally regulated in complicated pregnancies, suggesting that the gene-ELC interaction might be mediated by the placenta.

"These results open a new area for biomedical research which has been fundamentally neglected; ie, how to make a placenta biologically healthier," Dr. Weinberger said.

"Once we have answers to this question, we will be able to intervene to make the placenta less susceptible to the effects of its genome and the environmental vagaries of pregnancy," he concluded.

Dr. John Thoppil, president-elect of the Texas Association of Obstetricians and Gynecologists and an assistant professor at Texas A&M University's College of Medicine, commented, "These findings are interesting and very plausible. We have pretty compelling data already in epigenetics . . . For example, we have seen that babies born during the Dutch famine during World War 2 show higher rates of obesity and heart disease. Those kids were also more likely to have psychological diseases such as depression and schizophrenia. It is certainly possible that the placenta mediates some of these changes."

"Many of these insults seem worse if they occur early in pregnancy," he told Reuters Health by email. "Therefore, preconception care and optimization of health is important. It appears that lowering both physical and emotional stress during this time may improve long-term mental health in offspring."

Dr. Matthew Kim, a perinatologist at CareMount Medical in Poughkeepsie, New York, said in an email to Reuters Health, "the authors have convincingly demonstrated ... a plausible pathophysiologic basis for schizophrenia risk."

Like Dr. Weinberger, he noted that "factors that may be involved or modifiable in placental health are unknown. Therefore, there are no methods of placental surveillance and also no known interventions for placental health."

"If disease prevention is an important focus for medical research," he added, "then placental research is a foundational area of focus. That research is ongoing and will be of immeasurable importance to society."

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