Mental illnesses directly attributed to a single gene for the first time

Rare genetic variants in a single gene appear to increase the risk of developing mental health conditions, according to a new study.

Previous research indicated that both environmental and genetic risk factors contribute to a person's chances of developing a mental health condition such as schizophrenia (see BioNews 1083). However, this study found changes in the GRIN2A gene are directly linked to an increased prevalence of mood and anxiety disorders and schizophrenia. Furthermore, people with GRIN2A mutations often experience earlier onset of symptoms compared with other people who develop the same conditions.

'Our current findings indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness,' said Professor Johannes Lemke, head of Leipzig University Hospitals' Institute of Human Genetics and first author of the paper published in Molecular Psychiatry. '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 encodes a protein called GluN2A, a subunit of NMDA neurotransmitter receptors, which play an important role in healthy brain functions such as learning and memory. Alterations in GRIN2A that lead to changes in the activity of the receptor have been previously linked to epilepsy and intellectual disability.

The team used data from 121 people with genetic variants in GRIN2A and found that those with mutations which result in a lack of functional GluN2A protein had an 87-fold, 12-fold, and six-fold higher risk of developing psychotic, mood and anxiety disorders, respectively, compared to people with unaffected versions of the gene.

The researchers reported that four people with such mutations were treated with L-serine, an amino acid which can be found in foods such as eggs, meat and nuts, and has been shown to activate NMDA receptors in the brain. They reported that these people experienced improvements in their symptoms, indicating a possible avenue for treatment.

The authors acknowledge that a randomised controlled trial would be essential to confirm these findings. They also suggested that genetic testing might be beneficial for people diagnosed with mental health conditions, to improve diagnosis and potentially bring about personalised treatments:

'In addition to diagnostic certainty, establishing a genetic diagnosis of GRIN2A-related disorders can have therapeutic consequences,' they said.