Placental Genes Linked To Size Of Baby's Brain And Possibly To Schizophrenia Risk

Genomic scoring of schizophrenia-related genes in the placenta predicted the size of a baby's brain at birth and its rate of cognitive development, possibly portending schizophrenia later in life, researchers say.

In previous work, Dr. Daniel Weinberger of the Lieber Institute Institute for Brain Development, Johns Hopkins Medical Campus in Baltimore, identified an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs); the interaction was driven specifically by loci harboring genes highly expressed in the placenta in both normal and complicated pregnancies.

In the current study, the team analyzed whether fractionated GRSs and developmental disorders based on placental gene-expression loci (PlacGRSs) are linked with early neurodevelopmental outcomes in individuals with a history of ELCs.

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"It is a bit early to predict clinical action based on these findings, but (these) studies may yield a more granular, precise understanding of the specific genes that matter most," Dr. Weinberger said. "It may eventually be possible to identify especially high-risk pregnancies and newborns for heightened scrutiny and possibly interventions. This is aspirational at the moment."

As reported in Proceedings of the National Academy of Sciences, the team found that PlacGRSs are negatively associated with neonatal brain volume, both in singletons and offspring of multiple pregnancies; in singletons, the PlacGRSs are negatively associated with both cognitive development at one year and, less strongly, at age two, when cognitive scores become more sensitive to other factors.

Further analyses showed that the negative associations are stronger in males; found only with GRSs fractionated by placental gene expression; and not found in PlacGRSs for other developmental disorders, such as autism and attention deficit hyperactivity disorder.

"While the majority of individuals on this altered neurodevelopmental path likely 'canalize' back toward normal development," they note, "some may not be rescued and instead 'decanalize' toward illness."

Summing up, the authors state, "Higher PlacGRSs, in the presence of ELCs and particularly in males, alter early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia."

Dr. Weinberger said, "The goal of these studies is to launch a new chapter in obstetric medicine, aimed at placenta health and resilience. In this era of molecular/genetic medicine, going forward there may be more molecular approaches to reduce the risk of complicated pregnancy than what is currently available, which is mainly bedrest."

Dr. Henry Nasrallah, Professor of Psychiatry, Neurology, and Neuroscience and Director, Neuropsychiatry and Schizophrenia Programs at the University of Cincinnati College of Medicine, commented in an email to Reuters Health, "There is a large body of evidence that schizophrenia is a disorder of abnormal brain development during fetal life, cause by genetic and nongenetic - especially adverse perinatal - events during pregnancy. Hundreds of heritable risk genes have been identified so far using genome-wide association studies, as well as copy number variants (allele deletions or duplications) or mutations that shut down a gene completely, with no protein coding."

"What is particularly interesting about this report," he noted, "is the discovery that there is an interaction between adverse pregnancy events and the genes of brain development during fetal life in the placenta, which then translates into abnormal brain development, such as a smaller brain volume (reported by our research group in 1986) or thinning of the cortex (associated with cognitive impairment), which are now well known to be neurobiological features of schizophrenia."

"Thus," he said, "the genetic neurodevelopmental pathology in the brain that ultimately leads to psychotic illness in late adolescence or early adulthood is not always purely genetic or purely environmental, but an interaction between both."

In an earlier paper, Dr. Nasrallah suggested steps parents can take to lower the risk of abnormal fetal brain development that may lead to future psychosis.

—Marilynn Larkin

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