Scientists identify a gene that can directly cause mental illness

For decades, psychiatry has operated on a basic assumption: mental illness rarely traces back to a single broken gene.

Instead, risk is thought to emerge from the combined effects of thousands of tiny genetic shifts layered onto life experience. A new study challenges that view.

Researchers report that shutting down a single gene, GRIN2A, can directly trigger early-onset psychiatric illness. The potential effects include schizophrenia, anxiety, and mood disorders, with symptoms often beginning in childhood.

When one gene causes mental illness

By analyzing 235 people with GRIN2A mutations, the team found that so-called “null” variants – mutations that completely disable the gene – did not merely increase risk. They appeared capable of causing mental illness on their own by disrupting a specific brain signaling pathway.

The effect was striking. Compared with the general population, carriers of GRIN2A null variants showed an 87-fold increase in psychotic disorders.

Risk also rose nearly 12-fold for mood disorders and six-fold for anxiety. Symptoms sometimes emerged as early as eight to twelve years old.

“GRIN2A null appears to be the first monogenic cause of early onset and even isolated mental disorders, such as early onset schizophrenia,” wrote the researchers.

What GRIN2A does

GRIN2A encodes GluN2A, a subunit of the NMDA receptor – a core gatekeeper for the brain’s primary excitatory messenger, glutamate.

NMDA receptors are central to synaptic plasticity, learning, and circuit stability. Knock out GluN2A, and receptors are harder to assemble and deploy on neuronal membranes.

The result is a systemic signaling deficit that can plausibly drive hallucinations, paranoia, and mood dysregulation.

That mechanistic clarity is what sets GRIN2A apart from standard polygenic risk, where thousands of common variants each shift risk by a hair’s breadth.

Not all GRIN2A mutations behaved the same. People with missense changes – alterations that tweak the protein rather than erase it – had similar rates of seizures and developmental disability as null carriers, but far fewer psychiatric diagnoses.

The psychiatric burden clustered around variants that eliminate GluN2A function.

A pattern hidden in plain sight

The story emerged from a registry built for a different reason. Led by Johannes Lemke at the University of Leipzig Medical Center, the international team enrolled people tested for epilepsy or developmental delay, which are classic features of GRIN2A-related disorders.

When researchers followed up with clinicians to review psychiatric histories, a clear pattern emerged. Nearly all individuals with mental health diagnoses carried null variants (23 of 25), while only two of 37 with missense variants were affected.

To gauge the magnitude of risk, the group compared their cohort to 21 years of Finnish health records covering more than five million people. Even with small absolute numbers, the fold changes were hard to ignore.

According to Lemke, the findings indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness.

When symptoms stand alone

Remarkably, six individuals in the study developed mental illness without intellectual disability, and two had no epilepsy at all.

Under today’s guidelines, those patients would rarely receive genetic testing, because psychiatric symptoms alone usually don’t trigger sequencing.

The researchers argue that the true rate of isolated mental illness tied to GRIN2A null variants is likely underestimated – a blind spot created by who gets tested in the first place.

Another nuance emerged. More than 80 percent of GRIN2A null carriers with mental illness had epilepsy at some point.

Psychiatric symptoms typically appeared after seizures had resolved, and seizure history did not predict who developed psychosis, mood, or anxiety disorders.

A possible treatment path

The study also points toward a treatable pathway. Four people with GRIN2A-null-linked psychiatric symptoms received high-dose L-serine (up to 500 mg/kg/day) for more than a year.

All four improved. One person’s hallucinations stopped. Another’s overly suspicious symptoms remitted. A third had better control of behavioral problems. A fourth had fewer seizures.

Why L-serine? In the brain, it converts to D-serine, a co-agonist that activates NMDA receptors. If GRIN2A-dependent receptors are underperforming, flooding synapses with D-serine could partially restore signaling.

It’s a neat fit with longstanding observations that NMDA antagonists like ketamine and PCP can induce psychotic states in healthy people.

Prior D-serine trials in schizophrenia have yielded mixed results, most likely because those studies didn’t select patients by molecular cause. In a GRIN2A null subgroup, the signal may be much stronger.

GRIN2A’s shared biological pathway

GRIN2A joins a short list of high-confidence psychiatric genes. The well-known 22q11.2 deletion carries high schizophrenia risk but removes many genes and produces a recognizable developmental syndrome.

SETD1A is another strong risk gene, also often paired with severe neurodevelopmental issues.

Large-scale exome studies (like SCHEMA in 2022) flagged only about ten genes where rare variants markedly elevate schizophrenia risk, including GRIN2A (NMDA) and GRIA3 (AMPA), both pillars of glutamate signaling.

The convergence is hard to miss: in at least a subset of patients, glutamatergic hypofunction looks causal, not incidental.

Expanding psychiatric testing

Genetic testing is routine for unexplained seizures and developmental delays. It’s not standard for a 12-year-old with a first psychotic break or a 10-year-old with severe anxiety.

This study makes the case that, when onset is early or symptoms are severe, sequencing could uncover actionable biology – like a GRIN2A null variant – and open the door to targeted therapies such as L-serine.

That doesn’t mean most people with mental illness will have single gene answers. The vast majority won’t. But for a meaningful minority, the cause may be written in their DNA, and the treatment may be mechanism-based rather than trial-and-error.

A single gene that builds a key component of the brain’s glutamate receptors can, when switched off, initiate mental illness in childhood, sometimes without seizures or intellectual disability.

The finding challenges dogma, sharpens diagnosis, and hints at a workable intervention. More broadly, it shows how psychiatry can move from broad labels to precise biology, one defined mechanism at a time.

The study is published in the journal Molecular Psychiatry.

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