Genetics, Placenta and Schizophrenia: How It All Connects Before Birth
- Lidi Garcia
- Mar 24
- 5 min read
The environment inside the womb can influence a baby’s health for the rest of its life. In addition to nourishing the fetus, the placenta regulates signals that affect brain development. Research shows that factors such as maternal stress, infections and complications during childbirth can alter gene activity through DNA methylation, increasing the risk of psychiatric disorders such as schizophrenia, depression and bipolar disorder. A new genetic database has revealed that these changes in the placenta can influence the predisposition to these diseases, helping in prevention and new treatments in the future.
Scientists have long known that the environment inside the womb can profoundly influence a baby’s health, both at birth and throughout life.
There is a theory called DOHaD (Developmental Origins of Health and Disease) that suggests that conditions during pregnancy and the first years of life can affect the risk of diseases in adulthood.
One of the factors that most impacts this intrauterine environment is maternal stress. When a mother experiences intense stress during pregnancy, this can directly affect the baby, increasing the risk of developing cardiovascular and metabolic problems and even psychological disorders.
This effect occurs because stress releases hormones and inflammatory substances that can influence the development of the fetus.
The placenta is a temporary organ that plays an essential role during pregnancy, as it facilitates communication between the mother and the baby. It transports oxygen and nutrients to the fetus, eliminates substances that can be harmful and also regulates the release of hormones that are important for the baby's growth.
But the placenta does much more than that. Scientists have discovered that this organ can be an indicator of the environmental conditions of pregnancy and even predict health risks for the child in the future.
For this reason, some researchers call the placenta the "third brain", as it acts as a link between the mother's brain and the developing brain of the baby.
Schizophrenia is a serious psychiatric disorder that affects thinking, emotions and behavior. Many studies have already identified that genetics play an important role in the development of the disease. However, increasing evidence shows that the intrauterine environment can also influence this risk.
The neurodevelopmental hypothesis, proposed in 1987, suggests that changes in the formation of the fetal brain can create a vulnerability to developing schizophrenia later in life.
This means that, even if the disease does not manifest itself until adolescence or adulthood, the first changes can occur in the womb.
Different factors can increase this risk, such as:
Maternal infections during pregnancy (such as flu or other diseases that activate the mother's immune system).
Intense stress during pregnancy, which can affect the baby's hormonal balance and brain formation.
Complications during childbirth, such as lack of oxygen to the baby, pre-eclampsia or bleeding.
When the mother goes through any of these situations, her body releases inflammatory substances that can affect the development of the fetus' brain.
This can influence the way neurons are organized and how brain connections are formed, which can result in a greater predisposition to psychiatric disorders in the future.
In addition to genetics, scientists have discovered that the environment inside the womb can modify gene activity through a process called DNA methylation. DNA methylation is a mechanism that acts like a “switch,” regulating which genes are turned on or off in the body.
What makes the placenta so special is that it has a unique pattern of DNA methylation, unlike other organs in the body. This means that changes in methylation in the placenta can be specific and have long-lasting effects on the life of the baby.
For example, studies show that factors such as maternal smoking or obesity before pregnancy can alter DNA methylation in the placenta, affecting genes linked to the baby’s growth and immune system. These changes can have lifelong consequences, increasing the risk of metabolic and inflammatory diseases and even psychiatric disorders.
Scientists have discovered that some of these changes in DNA methylation may be linked to the risk of developing psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. This means that the genetic predisposition to these disorders may be influenced by the intrauterine environment via the placenta.
To better understand this relationship, researchers created a public database that analyzes changes in placental DNA. They collected genetic information from 368 fetal placenta samples and cross-referenced this data with large studies on psychiatric disorders.
The results showed that changes in placental methylation are linked to regions of DNA that influence the risk of psychiatric diseases. Some of these changes occur in genes related to fetal brain development.
The impact of placental methylation may be different between boys and girls, which may explain why some psychiatric disorders affect one gender more than the other.
These findings are important because they help us understand how genetics and the environment of pregnancy interact to influence mental health later in life.
This could lead to benefits such as:
Prevention: If doctors can identify risk factors during pregnancy, they can take steps to reduce the impact on the baby.
New treatments: Knowing how DNA methylation affects the brain could help develop more effective drugs for psychiatric disorders.
Improved prenatal care: If the placenta is indeed an indicator of future disease risk, more detailed screening during pregnancy could be used to predict and prevent mental health problems.
In summary, the research shows that the placenta may be a key piece in understanding how the intrauterine environment affects the mental health and neurodevelopment of the baby.
By studying these genetic and epigenetic changes, scientists are opening new doors to understanding and treating psychiatric disorders in the future.
READ MORE:
Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders
Ariadna Cilleros-Portet, Corina Lesseur, Sergi Marí, Marta Cosin-Tomas, Manuel Lozano, Amaia Irizar, Amber Burt, Iraia García-Santisteban, Diego Garrido-Martín, Geòrgia Escaramís, Alba Hernangomez-Laderas, Raquel Soler-Blasco, Charles E. Breeze, Bárbara P. Gonzalez-Garcia, Loreto Santa-Marina, Jia Chen, Sabrina Llop, Mariana F. Fernández, Martine Vrijheid, Jesús Ibarluzea, Mònica Guxens, Carmen Marsit, Mariona Bustamante, Jose Ramon Bilbao & Nora Fernandez-Jimenez
Nature Communications, volume 16, Article number: 2431 (2025)
Abstract:
Increasing evidence supports the role of the placenta in neurodevelopment and in the onset of neuropsychiatric disorders. Recently, mQTL and iQTL maps have proven useful in understanding relationships between SNPs and GWAS that are not captured by eQTL. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation. We construct a public placental cis-mQTL database including 214,830 CpG sites calculated in 368 fetal placenta DNA samples from the INMA project, and run cell type-, gestational age- and sex-imQTL models. We combine these data with summary statistics of GWAS on ten neuropsychiatric disorders using summary-based Mendelian randomization and colocalization. We also evaluate the influence of identified DNA methylation sites on placental gene expression in the RICHS cohort. We find that placental cis-mQTLs are enriched in placenta-specific active chromatin regions, and establish that part of the genetic burden for schizophrenia, bipolar disorder, and major depressive disorder confers risk through placental DNA methylation. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, the involvement of cell type-imQTLs, and the correlation of identified DNA methylation sites with the expression levels of relevant genes in the placenta.
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