Genetics is rarely as straightforward as a single gene driving a lone health outcome. But a new study has uncovered what could be a rare exception.
Changes to just one gene, called GRIN2A, have now been tied to psychiatric symptoms, including early-onset schizophrenia.
"Our current findings indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness," says co-lead author Johannes Lemke, a geneticist from Leipzig University in Germany.
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Mental health disorders, like major depression or schizophrenia, are generally thought to be influenced by hundreds or even thousands of interacting genetic variants. But perhaps that assumption isn't always true.
Recently, strong evidence has found that changes to the GRIN2A gene are associated with early-onset schizophrenia in childhood or early adolescence, sooner than the disorder typically presents.
Using a registry of the world's largest cohort of GRIN2A patients, the researchers led an international investigation into the effects of mutations in GRIN2A.
Among 121 individuals with likely disease-causing variants in the GRIN2A gene, the team found that 25 had a diagnosed mental disorder, including mood, anxiety, psychotic, personality, or eating disorders.
All but two of these individuals carried the "null" variant of GRIN2A, suggesting it was non-functional.
"We were able to show that certain variants of this gene are associated not only with schizophrenia but also with other mental illnesses," says Lemke.
"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."
What's more, while genetic mutations in the GRIN2A gene are typically associated with neurodevelopmental disorders, like epilepsy or intellectual disability, some of these participants showed only psychiatric symptoms.
This suggests that the GRIN2A change can drive isolated mental health disorders early in life without other neurodevelopmental issues.
"Genetic testing should be considered in the diagnostic work-up of affected individuals to improve diagnosis and potentially offer personalized treatment," the authors conclude.
GRIN2A encodes part of a glutamate receptor in the brain, which are involved in excitatory brain activity. Dysfunction of these receptors is closely associated with epilepsy and schizophrenia.
Four individuals in the current study had been treated in the past with L-serine, an amino acid that activates these glutamate receptors to help reduce seizures. Interestingly, all four participants experienced positive improvements to their mental health disorder after treatment.
One individual stopped experiencing hallucinations. Another showed improvements in their behavioral disorder. The remaining two showed remission from paranoid symptoms and a reduction in seizure frequency.
The small sample size limits the study, but it suggests that not all psychiatric disorders arise from numerous interacting genetic variants. Instead, some conditions could be precisely treated based on their genetic differences.
How exactly the GRIN2A gene may drive these disorders is another matter that needs further investigation.
The study was published in Molecular Psychiatry.