From Genetics to Personalized Treatment: Unique Gene Discovered Capable of Causing Mental Disorders

Researchers have discovered that rare and serious alterations in the GRIN2A gene can greatly increase the risk of developing mental disorders, such as schizophrenia, especially when they appear in childhood or adolescence. Some patients treated with L-serine, a substance capable of improving the functioning of a brain receptor related to this gene, showed improvement, indicating a possible new form of treatment targeted at the genetic profile.

Mental disorders affect millions of people worldwide and represent a profound impact not only on the lives of those who suffer from them, but also on the functioning of society. Diseases such as anxiety, depression, eating disorders, and schizophrenia can compromise well-being, autonomy, and relationships. Despite being so common, progress in treatments has been slow because we still know little about their deep biological causes.

In recent years, studies have shown that mental disorders result from a very complex combination of factors, including environment, life experiences, and, primarily, genetics. People who have close relatives with a mental disorder have a higher risk of developing one themselves.

This happens because genes can influence brain characteristics, such as how neurons communicate, how brain chemicals act, and how the brain develops during childhood and adolescence.

For a long time, it was believed that these diseases were caused by thousands of small changes in DNA, each contributing a very small risk, adding up like pieces of a puzzle. However, recent research has begun to reveal something additional: some rare genetic alterations, although much less common, can have a much greater impact, significantly increasing the risk of developing serious mental disorders.

An example of this are the so-called null variants, which can completely switch off an important gene, preventing the proper formation of certain proteins essential for brain function.

Among psychiatric disorders, schizophrenia, a condition marked by hallucinations, delusions, and changes in thought and behavior, is one of those with the greatest genetic influence. However, people with schizophrenia tend to have fewer children, which reduces the transmission of these variants across generations.

Thus, variants with a large impact often arise spontaneously, without being present in the parents. These new genetic changes, called de novo mutations, can affect large regions of chromosomes or specific genes important for the brain.

Some of these alterations have already been identified. For example, the deletion (or loss) of a specific segment of chromosome 22 is associated with an increased risk of schizophrenia and other conditions. Another important target of studies is the gene called GRIN2A, responsible for producing a specific part of a brain receptor called NMDA. This receptor participates in fundamental processes for communication between neurons, including memory, learning, and normal brain development.

A recent study analyzed 235 people worldwide with identified alterations in the GRIN2A gene. To better understand the associated psychiatric symptoms, scientists collected medical data throughout the lives of these individuals, including diagnostic history, age of symptom onset, relationship to epilepsy, and possible treatments.

They compared this information with data from a large population base to assess whether mental disorders were in fact occurring more frequently in this specific genetic population.

The results showed that individuals with complete loss of function of the GRIN2A gene had a much higher chance of developing various mental disorders, including schizophrenia, depression, anxiety, bipolar disorder, and behavioral disorders.

It was also observed that, in these cases, symptoms generally appeared much earlier than expected, often during childhood or adolescence, while in the general population these conditions tend to appear in adulthood.

The study also revealed an interesting relationship with epilepsy. Many people with alterations in the GRIN2A gene had epilepsy, but in most cases, mental disorders only emerged after the epileptic seizures had disappeared. This suggests that the origin of psychiatric symptoms is not directly linked to epileptic seizures, but rather to the critical role this gene plays in brain development.

The image shows how alterations in the GRIN2A gene are related to the onset of mental disorders throughout childhood and adolescence. The graphs at the top show that the general population hardly develops anxiety, depression, or psychosis before the age of 15, while people with a severe mutation in this gene (red line) show a progressive and significant increase in these disorders in the first years of life, especially between the ages of 8 and 15. The milder mutation (blue line) shows a slightly higher risk than the general population, but still much lower than that observed in severe mutations. The lower graphs confirm these findings by quantifying the risk: for those with a severe alteration in the GRIN2A gene (panel b), the risk of having anxiety, mood disorders, or psychosis can be up to tens of times higher than in the general population, indicating a strong and statistically reliable relationship; while in the case of mild mutations (panel c), the risk is not significantly higher. In summary, the image demonstrates that severe mutations in the GRIN2A gene are strongly associated with the early development of mental disorders, while milder mutations appear to have little or no measurable impact on risk.

Another promising aspect of the research was the analysis of a possible treatment. The GRIN2A gene is linked to the functioning of the NMDA receptor, and a substance called L-serine is known to help this receptor function better. Four people with mental disorders associated with alterations in the gene were treated with L-serine and showed improvement in symptoms.

Although the number is small, the result is important because it paves the way for the development of personalized treatments based on the specific type of genetic alteration in the patient.

This set of findings suggests something innovative: for the first time, a single gene may be associated with severe and early mental disorders, such as schizophrenia, even when there are no other evident clinical symptoms. This means that genetic testing may be used in the future to aid in diagnosis and the selection of specific treatments, marking a significant step towards precision medicine in mental health.

“Our current results indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness. This differentiates it from the polygenic causes of such disorders that were previously assumed,” says Professor Johannes Lemke, lead author of the study and Director of the Institute of Human Genetics at the Leipzig University Medical Center.

LEIA MAIS:

GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy

Johannes R. Lemke, Andrea Eoli, Ilona Krey, Bernt Popp, Vincent Strehlow, Dirk A. Wittekind, Anna-Leena Vuorinen, Hesham M. Aldhalaan, Sarah Baer, Anne de Saint Martin, Trine B. Hammer, Isabella Herman, Frauke Hornemann, Trine Ingebrigtsen, Damien Lederer, Gaetan Lesca, Dana Marafie, Mikael Mathot, Jill A. Rosenfeld, Rikke S. Møller, Helenius J. Schelhaas, Chelsey Stillman, Alessandro Orsini, Anup D. Patel, Juliette Piard, Pierangelo Veggiotti, Danique R. M. Vlaskamp, Sarah Weckhuysen, Stephen F. Traynelis, Tim A. Benke, Henrike O. Heyne, and Steffen Syrbe 

Molecular Psychiatry (2025). 

https://doi.org/10.1038/s41380-025-03279-4

Abstract:

Rare genetic factors have been shown to substantially contribute to mental illness, but so far, no precision treatments for mental disorders have been described. It was recently identified that rare variants in GRIN2A encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) confer a substantial risk for schizophrenia. To determine the prevalence of mental disorders among individuals with GRIN2A-related disorders, we enquired the presence of psychiatric symptoms in 235 individuals with pathogenic variants in GRIN2A who had previously enrolled in our global GRIN registry. We identified null variants in GRIN2A (GRIN2Anull) to be significantly associated with a broad spectrum of mental disorders including schizophrenia compared to a longitudinal population cohort (FinRegistry) as well as missense variants (GRIN2Amissense). In our cohort, GRIN2Anull-related mental disorders manifest in early childhood or adolescence, which is substantially earlier than the average adult onset in the general population. In 68% of co-incident epilepsy and mental disorder, mental disorders start after epilepsy offset and the age of epilepsy offset correlated with mental disorder onset. GRIN2Anull-related phenotypes appear to occasionally even manifest as isolated mental disorder, i.e. as schizophrenia or mood disorder without further GRIN2A-specific symptoms, such as intellectual disability and/or epilepsy. As L-serine is known to mediate co-agonistic effects on the NMDAR, we applied it to four individuals with GRIN2Anull-related mental disorders, all of whom experienced improvements of their neuropsychiatric phenotype. GRIN2Anull appears to be the first monogenic cause of early-onset and even isolated mental disorders, such as early-onset schizophrenia. Genetic testing should be considered in the diagnostic work-up of affected individuals to improve diagnosis and potentially offer personalized treatment as increasing brain concentrations of NMDAR co-agonists appears to be a promising precision treatment approach successfully targeting deficient glutamatergic signaling in individuals with mental disorders, i.e. due to GRIN2Anull.