Source: © Francois du Plessis -
Source: © Francois du

Scientists at the Lieber Institute for Brain Development (LIBD) and at the University of North Carolina (UNC) School of Medicine, have found that genetic scoring of schizophrenia-related genes in the placenta can predict the size of a baby’s brain at birth and its rate of early cognitive development, which—dependent on other factors—may lead to schizophrenia later in life. The researchers analyzed newborn MRI scans at UNC, together with cognitive development measures for the first two years of life, to uncover the link, which, they noted, was more significant in males.

“By identifying the specific genes activated in the placenta that appear to be unique for schizophrenia risk, we have zeroed in on a set of biological processes that could be targeted to improve placental health and reduce schizophrenia risk,” said Daniel R. Weinberger, MD, CEO & Director of the Lieber Institute. “To date, prevention from early in life has seemed unapproachable if not unimaginable, but these new insights offer possibilities to change the paradigm.”

Weinberger and colleagues describe their findings in Proceedings of the National Academy of Sciences (PNAS), in a paper titled “Placental genomic risk scores and early neurodevelopmental outcomes.”

Tracing the early paths leading to developmental disorders is critical for prevention, the authors wrote. “Understanding the deviations from normal trajectories of brain development may be crucial for predicting illness and for prevention.” In fact, epidemiological studies have consistently identified early precursors such as complications during pregnancy and developmental milestone delays. The team’s reported study builds on more than 30 years of scientific evidence indicating that the risk for schizophrenia, a disorder first typically diagnosed in early adult life, begins much earlier in life, even during prenatal life.

Many studies have shown that complications during pregnancy, such as infections and malnutrition, can increase the probability of schizophrenia. Recent genetic studies have in addition shown that many of the genes found to be risk factors for schizophrenia are abundantly expressed in the brain before birth, adding to the circumstantial evidence that early life is important. “We previously identified an environmental context in early life in which genomic risk for schizophrenia may enhance disease susceptibility,” the researchers continued.

In 2018, scientists at the Lieber Institute reported that some of these genes also were activated in the placenta, and especially if the pregnancy was complicated, for example by conditions like pre-eclampsia or intrauterine growth restriction. “In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence,” they explained.

These earlier results suggested that placenta health may be a factor in schizophrenia risk, and in particular, if the offspring is a male, the effects are greater. They also led the investigators to further explore the biological interplay between placental health and neurodevelopment. The team’s newly reported work was designed to investigate whether, in the presence of a history of ELCs, placental genomic risk for schizophrenia was associate with early neurodevelopmental outcomes, up to 2 years of age. “We found that placental genomic risk is negatively associated with neonatal ICV [intracranial volume] in a sample of singletons and offspring of multiple pregnancies and, in singletons, correlates with worse cognitive development at 1 y and shows a directionally similar but attenuated effect at 2 y,” they wrote.

The investigators also found that in adult individuals with schizophrenia, the same genetic scores that represent placental gene expression predicted brain size measured on MRI scans, and the directionality of the relationship was the same as that found in the neonates. This was not found in individuals who were the normal controls in the study of adult subjects. “Our results further suggest that, at least in the presence of ELCs, genetic variants relevant for the placental response to stress, but eventually associated with schizophrenia, may cumulatively affect brain growth, deviating the neurodevelopmental trajectory toward the eventual disease phenotype.”

However, the team acknowledged, the impact of various genetic and environmental factors means that the future development of schizophrenia is by no means a given in these children. Weinberger notes that most of the children with higher schizophrenia gene scoring in the placenta will not develop schizophrenia because other genetic and environmental factors will compensate for these placental effects later in development. But, he says, in principle, individuals who have other schizophrenia genetic risk factors and early life complications during pregnancy may not be able to compensate and will develop the illness, particularly if they are males. As the authors explained, “While the majority of individuals on this altered neurodevelopmental path likely “canalize” back toward normal development, some may not be rescued and instead “decanalize” toward illness.”

The UNC and LIBD researchers also looked for similar relationships in other neurodevelopmental disorders. Complicated pregnancies increase the risk for autism, ADHD, and intellectual difficulties, so scientists examined the relationship between brain size at birth and cognition during the next two years and genetic scores representing risk genes for these and other developmental disorders and traits expressed in the placenta. None of these disorders showed similar associations to those found with schizophrenia, suggesting that the effect of schizophrenia risk placental gene expression may have a unique relationship to early brain development.

“This is further evidence that early life matters in schizophrenia and the placenta plays a bigger role than we imagined,” said Weinberger. “Measuring schizophrenia genetic scores in the placenta combined with studying the first two years of cognitive developmental patterns and early life complications could prove to be an important approach to identify those babies with increased risks. Understanding the trajectories leading to neurodevelopmental disorders is a big challenge, but a necessary one to design strategies aimed at prevention.”

The researchers concluded, “Specific strategies of prevention may benefit from understanding the unique placental effects of schizophrenia genomic risk and from defining which factors contribute to decanalize the neurodevelopmental trajectories of individuals with a history of risk factors who develop schizophrenia.”

John H. Gilmore, MD, Eure Distinguished Professor and Vice Chair for Research in the Department of Psychiatry and UNC’s lead investigator on the study, said “I read Dr. Weinberger’s classic paper laying out the neurodevelopmental hypothesis of schizophrenia during my psychiatry residency. It inspired me to ultimately create the UNC Early Brain Development Study to better understand early childhood brain development and its relationship to risk for schizophrenia. Thirty years later, it has been a career highlight to collaborate with Dr. Weinberger and his team on this study, one that advances our understanding of the complex interactions of genetic and environmental risk factors in the earliest phases of human brain development.”

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