This research offers a new insight into the origins of schizophrenia by highlighting the placenta as a key factor in the development of the disorder. Rather than acting solely in the brain, more than 100 genes associated with schizophrenia risk appear to influence the functioning of the placenta, where they help regulate the exchange of nutrients between mother and baby.
The recent study of the placenta’s role in the development of schizophrenia challenges the traditional view that risk genes associated with the disorder directly affect the brain.
The placenta, the first organ to form in the fetus, serves as a vital link between mother and baby, providing oxygen and essential nutrients, eliminating waste products, and protecting the fetus from infections and harmful immune responses.
These functions are essential for healthy brain development, and placental dysfunction has been linked to increased risks of neuropsychiatric disorders such as schizophrenia.
In detail, schizophrenia affects about 1% of the world’s population and is more prevalent in males. Although diagnosis usually occurs in adolescence or early adulthood, the roots of the disorder appear to be linked to early developmental processes.
Research has shown that schizophrenia has an estimated heritability of 50% to 80%, and genome-wide association studies (GWAS) have identified hundreds of genetic variants linked to the disorder. These variants may explain about 7.3% of the genetic predisposition, but science is still investigating how these variants alter biological functioning to increase the risk of the disorder.
To better understand these mechanisms, scientists at Johns Hopkins University School of Medicine used methods such as the Transcriptome-Wide Association Study (TWAS) and Summary data-based Mendelian Randomization (SMR), their results were published in the journal Nature Communications.
TWAS and SMR are bioinformatics and statistical genetics tools that allow us to investigate how genetic variants influence the expression of specific genes and, in turn, affect the risk of developing complex diseases, such as schizophrenia.
Both help to clarify how genetic predisposition relates to the biological characteristics of a specific organ or tissue and the risk of diseases, but they do so in different ways.
They used samples from 147 healthy placentas at term to derive candidate placental causal genes that confirmed SMR; to look for specific associations of placenta and schizophrenia, they performed an analogous analysis in the brain on 166 samples and additional placental TWAS for other disorders/traits.
These approaches analyze the expression of risk genes not only in the brain but also in the placenta, identifying the impact of these variants on the placenta’s ability to capture and exchange nutrients with the maternal bloodstream.
The researchers found that more than 100 risk genes for schizophrenia appear to influence placental function more directly than brain development.
Another point of interest in the study is the impact of complications during pregnancy, such as infections. The research showed that the interaction between genetic factors and perinatal complications can amplify the risk of schizophrenia by up to five times.
In particular, placentas from mothers who contracted COVID-19 during pregnancy showed increased expression of these risk genes, suggesting that SARS-CoV-2 infection may interfere with placental processes and contribute to the development of neuropsychiatric disorders.
The researchers found that schizophrenia genes influence a critical function of the placenta to detect nutrients in the mother's bloodstream, including oxygen, and exchange nutrients based on what it finds.
Schizophrenia risk genes are less highly expressed in placental cells that form the core of this maternal-fetal nutrient exchange, called trophoblasts, negatively affecting the placenta's role in nourishing the developing fetus. The paper also identifies several genes in the placenta that are causal factors for diabetes, bipolar disorder, depression, autism, and attention deficit hyperactivity disorder, or ADHD.
However, the scientists found far more genetic associations with genes for schizophrenia than for any of these other disorders.
The scientists also found interesting sex-based differences in placental risk genes. Different genes were associated with schizophrenia risk based on whether the placenta originated from a boy or a girl. In pregnancies with boys, inflammatory processes in the placenta appear to play a central role.
Previous research has shown that men are more vulnerable than women to prenatal stress. In general, developmental disorders such as schizophrenia occur more frequently in men and boys.
Based on these findings, the study opens new avenues for schizophrenia prevention by focusing on placental health as a potential intervention point. Assessing the expression of specific genes in the placenta and monitoring the health of the organ during pregnancy could allow doctors and scientists to develop prevention strategies that reduce the impact of the disorder, offering an innovative preventive approach that complements brain-focused research.
READ MORE:
Prioritization of potential causative genes for schizophrenia in the placenta.
Ursini G, Di Carlo P, Mukherjee S, et al.
Nat Commun 14, 2613 (2023). https://doi.org/10.1038/s41467-023-38140-1
Abstract:
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 the 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 the 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 the study of the brain alone.
Коментарі