In a breakthrough study, scientists have discovered that a variant in one gene, GRIN2A, can directly cause mental illness – something previously believed to be the result of several mutations working together. What’s more, these conditions often present in childhood instead of more commonly during adulthood.
An international study led by the Institute of Human Genetics at the University of Leipzig Medical Center collected data from 235 individuals with known pathogenic GRIN2A variants, and were able to use 196 of the samples. Of these, 121 individuals had clear information about whether they had been diagnosed with a mental disorder. Although the full analysis was on people aged from one to 62 years, because it included parents and other relatives who were only tested after a child was diagnosed, the psychiatric findings come mainly from the originally diagnosed individuals, who were typically children and teenagers (cohort median age of 12 years).
They were split into 84 with GRIN2A “null” variants – which disrupt the gene entirely – and 37 with “missense” mutations, which alter but don’t totally knock out the protein. Among the null carriers, 23 out of 84 – 27.4% – had at least one mental illness, which is a significantly high number given the young average age of participants. These included 13 mood disorders, 12 anxiety disorders and eight psychotic disorders, with some individuals diagnosed with more than one condition. By contrast, only two out of 37 missense carriers had a mental disorder, indicating that the null variants are associated with roughly a six-fold increase in risk compared to those with slightly altered GRIN2A.
“Our current findings indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness,” said lead author Professor Johannes Lemke, Director of the Institute of Human Genetics at the University of Leipzig Medical Center. “This distinguishes it from the polygenic causes of such disorders that have been assumed to date.”
To understand how unusual this level of risk is, the researchers compared their cohort to the country-wide Finnish population database FinRegistry of more than five million people. They restricted their analysis to childhood and early adolescence, because this is when symptoms appeared in the GRIN2A-null cohort (mental illness conditions generally present much later in life). Children with null variants were 87 times more likely to develop a psychotic disorder and six times more likely to have an anxiety disorder by age 12, and around 12 times more likely to develop a mood disorder by age 11. It’s worth noting that childhood-onset psychosis is extremely rare in the general population, meaning these risk statistics are some of the largest ever seen in psychiatric genetics.
“We were able to show that certain variants of this gene are associated not only with schizophrenia but also with other mental illnesses,” said 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.”
GRIN2A mutations have long been linked to epilepsy, intellectual disability or speech disorders in children, however, in this case the researchers found that six individuals with GRIN2A-null variants had no history or evidence of those neurological conditions but still presented with a psychiatric disorder. The gene itself is key to regulating the electrical excitability of nerve cells – and, in the case of this study, some variants resulted in reduced activity of the NMDA receptor, which plays an important role in signal transmission in the brain.
Because GRIN2A helps build part of the NMDA receptor, which is already known to play a role in disorders like schizophrenia, the researchers tested whether boosting this receptor’s activity might help individuals’ symptoms. Four people with GRIN2A-null mutations and psychiatric symptoms were given high doses of L-serine, a supplement the brain turns into a natural NMDA receptor (NDMAR) activator. While it’s worth noting that this was not a controlled trial, all individuals had improvements – hallucinations and paranoia disappeared, while one had fewer seizures. This, however, needs further study to consider whether L-serine is a viable treatment option.
“As L-serine is known to mediate co-agonistic effects on the NMDAR, we applied it to four individuals with GRIN2A-null-related mental disorders, all of whom experienced improvements of their neuropsychiatric phenotype,” the researchers wrote. “GRIN2A-null appears to be the first monogenic cause of early-onset and even isolated mental disorders, such as early-onset schizophrenia.”
Of course, psychiatric disorders are not all the result of GRIN2A variants, and it still stands that the interplay between various genes as well as external factors (environmental, lifestyle) are behind the development of various mental health conditions. But this new research presents evidence of a single-gene cause – and makes a case for early childhood genetic testing in order to assess risk.
The study was published in the Nature journal Molecular Psychiatry.