Broken copies of a key brain gene may drive schizophrenia and other disorders

A new study has identified specific genetic variants that confer a high risk for developing schizophrenia and other mental disorders, with symptoms often appearing in childhood. The research, published in Molecular Psychiatry, suggests that for some individuals, a single gene may be a primary driver of their condition, a finding that could shift perspectives on the origins of mental illness.

Mental disorders represent a wide array of conditions with complex causes. While environmental factors play a part, genetics are known to contribute substantially. For many years, the prevailing scientific view has been that most common mental illnesses, like schizophrenia or major depression, are polygenic. This means their genetic basis is thought to arise from the combined small effects of thousands of different genes, rather than a single powerful one. Identifying these risk factors has been a major goal of psychiatric genetics.

This new investigation was conducted by a large international consortium of researchers, coordinated by scientists at the Institute of Human Genetics at the University of Leipzig Medical Center and the University of Heidelberg in Germany. This group has spent years building a registry of individuals with genetic variations in a family of genes known as GRIN genes. This registry provided the foundation for their systematic examination of one gene in particular, GRIN2A, and its potential connection to mental health.

The GRIN2A gene contains the instructions for making a protein called GluN2A. This protein is one component of the N-methyl-D-aspartate, or NMDA, receptor, which is found on the surface of brain cells. NMDA receptors are essential for healthy brain function, playing a central part in learning, memory, and the communication between neurons.

Previous research had already linked alterations in the GRIN2A gene to a range of neurodevelopmental conditions, most notably epilepsy and speech disorders. Recent large-scale genetic analyses also hinted at a possible association with schizophrenia, prompting the current team to explore this link in greater detail.

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To conduct their study, the researchers drew upon their international registry of 235 individuals with known variants in the GRIN2A gene. They contacted the treating physicians for each person and used a standardized questionnaire to gather information about their mental health history. They requested details on any diagnoses of mental disorders, such as anxiety, mood, or psychotic disorders, along with the age at which symptoms first appeared. After excluding cases with incomplete information, their final analysis focused on a cohort of 121 individuals.

The team first categorized the genetic variants into two main types. One type, known as missense variants, involves a change to a single building block of the gene, which alters the final protein product but does not necessarily disable it. The other type, called null variants, includes changes that effectively break the gene, preventing a functional protein from being produced at all.

The analysis revealed a clear distinction between these two groups. Among the 84 individuals with null variants, 23 were diagnosed with a mental disorder. In contrast, only two of the 37 individuals with missense variants had a mental disorder. This showed a significantly higher probability of mental illness associated with the null variants.

To understand the magnitude of this risk, the researchers compared their findings to a large control group. They utilized data from FinRegistry, a comprehensive database containing health records for the entire population of Finland. This allowed them to compare the rate of new mental disorder diagnoses in their GRIN2A cohort to that of the general population over time. The results of this comparison were pronounced for individuals with GRIN2A null variants.

The data showed that these individuals had a dramatically elevated incidence of mental illness, particularly during childhood and adolescence. Compared to the control population in the same early age ranges, people with GRIN2A null variants had an 87-fold higher incidence of psychotic disorders, a nearly 12-fold higher incidence of mood disorders, and an almost 6-fold higher incidence of anxiety disorders. This early onset is a notable departure from the typical presentation of many psychiatric conditions, which often emerge in late adolescence or early adulthood.

The study also uncovered an unusual relationship between epilepsy and mental illness in this group. For individuals who had experienced both conditions, the researchers noted a correlation between the age at which their epilepsy subsided and the age their mental disorder began. In more than half of these cases, the psychiatric symptoms appeared after their seizures had stopped.

Additionally, the team identified six individuals whose only major symptom from their GRIN2A null variant was a mental disorder. They did not have the intellectual disability or epilepsy commonly associated with the gene, suggesting that a psychiatric condition can be the sole manifestation.

The researchers also gathered observational data on a potential treatment. Four individuals in the cohort with GRIN2A null variants and mental disorders had been treated with L-serine, a naturally occurring amino acid that can be purchased as a dietary supplement. L-serine is known to help activate NMDA receptors in the brain. Retrospective reports from their physicians indicated that all four experienced improvements in their symptoms, including a reduction in hallucinations and paranoid thoughts.

The study has some limitations. The group of individuals with GRIN2A variants was primarily identified through genetic testing for childhood neurological conditions like epilepsy. This approach may have biased the sample toward more severe cases and could mean the prevalence of isolated mental disorders caused by these variants is underestimated in the wider population. The information on mental health was also collected retrospectively, which can be less precise than data collected in a forward-looking, or prospective, manner.

Finally, the positive results from L-serine treatment are based on a very small number of cases and were not part of a randomized, placebo-controlled trial, which is the standard for proving a treatment’s effectiveness.

Future research will need to confirm these findings in larger and more diverse populations. A formal clinical trial would be required to establish whether L-serine is a genuinely effective therapy for the psychiatric symptoms associated with GRIN2A null variants. The study’s results may also encourage a re-evaluation of the role of genetic testing in psychiatry. If single genes can confer such a high risk for early-onset mental illness, genetic diagnosis could become a more common tool, potentially paving the way for targeted, personalized treatments.

The study, “GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy,” was authored by 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.