Scientists have identified the first specific gene known to directly cause mental illness on its own, upending the prevailing medical consensus that psychiatric disorders stem exclusively from the interaction of hundreds or thousands of genetic variants.
An international team led by Leipzig University has identified the first gene that—by itself—can directly cause psychiatric illness, upending the view that such disorders always stem from many genetic hits acting together.
In a study published in the journal Molecular Psychiatry, an international team led by researchers at Leipzig University in Germany found that mutations in a gene called GRIN2A are linked to psychiatric symptoms, including early-onset schizophrenia, mood disorders and anxiety.
“Our current findings indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness,” said Professor Johannes Lemke, the study’s co-lead author and Director of the Institute of Human Genetics at the University of Leipzig Medical Centre. “This distinguishes it from the polygenic causes of such disorders that have been assumed to date.”
Study Findings
Professor Lemke established an international registry containing the largest known cohort of GRIN2A patients worldwide to conduct the investigation. The researchers performed a statistical analysis of data from 121 individuals possessing likely disease-causing variants of the gene.
The team discovered that 25 of these individuals had a diagnosed mental disorder, including psychotic, mood, anxiety, personality, or eating disorders. Notably, all but two of these subjects carried a “null” variant of the gene, suggesting it was non-functional.
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While genetic mutations in GRIN2A are typically associated with neurodevelopmental disorders such as epilepsy or intellectual disability, the study revealed an unexpected finding: some participants exhibited only psychiatric symptoms without other neurodevelopmental issues.
Furthermore, the symptoms manifested significantly earlier than usual.
“What is striking is that, in the context of a GRIN2A alteration, these disorders already appear in childhood or adolescence – in contrast to the more typical manifestation in adulthood,” Professor Lemke said.
Mechanism and Treatment
The GRIN2A gene encodes part of a glutamate receptor in the brain known as the NMDA receptor. This receptor helps regulate the electrical signalling and activity of nerve cells, which is essential for communication between brain cells. Dysfunction in these receptors is closely associated with conditions such as epilepsy and schizophrenia.
The study found that certain variants reduced the function of the NMDA receptor. However, this discovery also pointed toward a potential treatment.
Professor Lemke collaborated with Dr Steffen Syrbe, a Professor at the Heidelberg Medical Faculty and paediatric neurologist at Heidelberg University Hospital. The pair have worked together for nearly 15 years in clinical and research settings to understand disorders involving the brain’s glutamate receptor.
In an early treatment effort involving four individuals from the study, doctors administered L-serine, a dietary supplement and amino acid known to activate glutamate receptors and reduce seizures. All four participants experienced positive improvements in their mental health.
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In terms of results, one patient reported a complete end to hallucinations, while another saw their behavioral symptoms subside. The remaining two patients showed a remission of paranoid symptoms alongside a reduction in seizure frequency.
Implications for Diagnosis
The authors concluded that while the sample size was limited, the findings suggest that not all psychiatric disorders arise from a complex mix of genetic influences. Instead, some conditions may be treated precisely based on specific genetic differences.
“Genetic testing should be considered in the diagnostic work-up of affected individuals to improve diagnosis and potentially offer personalized treatment,” the authors wrote.
According to the World Health Organization (WHO), nearly one in seven people globally lived with a mental illness in 2021, with anxiety and depression being the most frequent conditions. While having a close family member with a mental illness remains one of the strongest predictors of risk, this research opens new avenues for understanding the genetic roots of these conditions.
The study was published in Molecular Psychiatry.