The Genetic Impact of Childhood Trauma on Schizophrenia

Schizophrenia is a rare brain disorder, occurring in one percent of the U.S. population¹. It is associated with hallucinations, delusions, disorganized speech and trouble with thinking and focus². A key characteristic that is often associated with schizophrenia is hallucinations, which is seeing things that are not real. People who have parents with the disease often inherit genes that cause changes in the brain³. Environmental stressors during early childhood further influence this susceptibility. Childhood trauma has a large effect on brain development and leaves lasting genetic changes within the brain. 

This paper explores how early-life hardships are linked to genetic vulnerability, particularly in gene expression, focusing on trauma-induced gene expression changes that may contribute to the development and progression of this condition. 

Background 

Schizophrenia is a heritable, neurocognitive disorder. Previous studies have suggested that the heritability of this disease is around 60-80%.⁴ Genetic makeup plays a large role in the development of this mental illness. Although it has high heritability, genes alone do not determine its onset, as environmental triggers like trauma play a key role. Trauma is an emotional response to an event such as a crime, natural disaster, physical or emotional abuse, neglect, experiencing or witnessing violence.⁵ Exposure to chronic stress disrupts the hypothalamic-pituitary-adrenal (HPA) axis and the corticotropin-releasing factor (CRF), both of which are important for stress response. Under normal conditions, CRF is released from the hypothalamus, stimulating the release of the adrenocorticotropic hormone from the pituitary gland, triggering cortisol release from the adrenal gland. Within this system, cortisol acts as a signal to the hypothalamus and pituitary gland to shut down the stress response.⁶ 

However, hardships in early childhood disrupt this system permanently. Studies in animals and humans have shown that early stress increases CRF production which impairs the ability of cortisol to properly regulate stress responses.⁷ As a result of this dysregulation, people who are exposed to distressing events experience elongated stress-response. However, in their adult life, their cortisol levels may be low. Yet, adults who have experienced traumatic events still show exaggerated stress responses. Over time, this persistent activation leads to lasting damage to the hippocampus; persistent traumatic stress leads to progressive neuron loss and impaired neurogenesis, the generation of neurons, over time. Consequently, cortisol dysregulation can lead to structural brain changes, such as a decreased performance of the prefrontal cortex, amygdala hyperactivation and decreased hippocampus function, all of which affect memory, emotional regulation and cognitive function. 

With respect to the disorder, these structural changes are significant. The mental illness has been linked to HPA axis abnormalities, including altered and diminished cortisol regulation. The hippocampus and prefrontal cortex are major sites of dysfunction within the disorder.⁸ Chronic stress exposure often results in a hyperactive and poorly controlled stress response system, contributing to vulnerability to psychotic symptoms seen in the disorder. 

Gene Expression and Epigenetics 

Gene expression is the process in which information encoded in a gene is used to produce functional genetic products, mainly proteins. This occurs through two stages: transcription and translation, where DNA is first copied into a messenger RNA (mRNA) and the mRNA is then translated into proteins. Transcription converts the genetic information into a form that can leave the nucleus and guide protein synthesis. Translation occurs when the mRNA is read by ribosomes and converted into proteins.⁹  The term epigenetics refers to changes in gene function that are heritable, but do not consist of changes to the DNA sequence. In current literature, epigenetic modifications are described as histone modifications and amino acid alterations post-translation.¹⁰ Adversity can alter gene expression without changing the DNA sequence, increasing the risk of psychological symptoms associated with schizophrenia. 

Genes such as FK506-binding protein 51, FKBP51, and NR3C1, the glucocorticoid receptor, act as moderators of the HPA axis and stress response. FKBP51 regulates glucocorticoid receptor sensitivity which acts as a switch for how cells respond to increased cortisol, the primary stress hormone. The glucocorticoid receptor aids in activating the body’s stress response once the stimulus has passed. NR3C1 has a similar function to the negative feedback regulation of the HPA axis. 

Research has shown that childhood maltreatment can lead to epigenetic changes, particularly via DNA methylation of the NR3C1 gene, resulting in altered glucocorticoid receptor expression.¹¹ Through DNA methylation, the NR3C1 gene becomes less active; as a result, fewer glucocorticoid receptors are made. This has dire consequences in the body, because fewer receptors cause the body to be unable to shut down the HPA axis and stress response¹². More importantly, methylation patterns and HPA axis dysregulation have been observed in individuals diagnosed with this disease, suggesting that early childhood maltreatment leaves a lasting impact. 

A similar effect occurs in the FKBP51 gene. The FKBP51 protein is essential for regulating stress. During times of stress, the FKBP51 gene is activated through glucocorticoid receptor signaling. The glucocorticoids bind to the receptor as it moves into the nucleus and transcribes the FKBP51 gene.¹³In turn, this makes the FKBP51 protein less sensitive. Childhood stress often results in changed FKBP51 gene performance, resulting in a dysregulation of the gene, leading to increased levels of cortisol within the body. 

Regions such as the prefrontal cortex and hippocampus are important centers for memory, function, and decision making and have notable changes¹⁴. These include differences in the expression of genes involved in neuro-inflammation, synaptic plasticity, and neurotransmission. Moreover, the earlier that adversity is experienced, the more significant the variable gene expression is within these brain regions. Chronic exposure to troubling events often results in permanent and stronger epigenetic alterations.¹⁵ 

Conclusion 

Understanding how trauma changes gene expression could help explain why some people with a genetic marker develop schizophrenia, while some do not. In addition, it may bring light to new ways to prevent the onset of the disease. These “markers” could help identify those at risk for developing it before symptom onset.

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Written by Sydney Martinez

References 

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https://www.psychiatry.org/patients-families/schizophrenia. Accessed 24 April 2025.

² Mayo Clinic Staff. “Schizophrenia - Symptoms and causes.” Mayo Clinic, 16 October 2024, https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-20354443. Accessed 24 April 2025. 

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¹¹ McGowan, Patrick O., et al. “Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.” Nature Neuroscience, vol. 12, 2009, pp. 342-348. Nature Neuroscience, https://www.nature.com/articles/nn.2270#citeas.

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https://pmc.ncbi.nlm.nih.gov/articles/PMC9957055/. 

¹⁵ Jiang, Shui, et al. “Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma.” Frontiers in psychiatry, vol. 10, 2019. National Library of Medicine, 

https://pmc.ncbi.nlm.nih.gov/articles/PMC6857662/.