The First Single Gene Directly Causing Mental Illness:
Scientists Identify First-Ever Single Gene That Can Directly Cause Mental Illness
By Olga Vagin, PhD, Professor, School of Medicine and Nils Lambrecht, MD, PhD, Professor, School of Medicine
Mental health disorders, such as major depression and schizophrenia, are usually associated with hundreds or even thousands of genetic variants (1). However, a recent study has found that mutations in a single gene called GRIN2A are associated with early-onset schizophrenia in childhood or early adolescence. The results of this study, published in Molecular Psychiatry (2), indicate that GRIN2A is the first known gene that, when changed or disrupted, can cause a mental illness.
The GRIN2A gene is responsible for the synthesis of one of the subunits of N-methyl-D-aspartate (NMDA) receptor, which is found almost exclusively in the brain (Fig. 1). NMDA receptors play an integral role in the transmission of signals between neurons in our brain. They regulate synaptic plasticity, a neuronal mechanism crucial for memory. NMDA receptors are also important for long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission, which is a basis for certain kinds of memory and learning.
Multiple genetic variants of the GRIN2A gene have been identified (Fig. 2). Twelve of them are found to be associated with various neurologic diseases (pathogenic variants shown in red color in Fig. 2), and multiple variants are of uncertain significance (shown in yellow in Fig. 2).
Using a registry of the world’s largest cohort of GRIN2A patients, the researchers explored the effects of mutations in GRIN2A. Among 235 individuals with pathogenic variants of GRIN2A, the researchers identified “null” (dysfunctional) variants of GRIN2A significantly associated with a broad spectrum of mental disorders, including schizophrenia, mood disorders, anxiety, psychotic disorders, personality disorders, or eating disorders.
The “null” variant of GRIN2A appears to be the first monogenic cause of early-onset mental disorders, such as early-onset schizophrenia. The authors of the paper suggest considering genetic testing of affected individuals to improve early diagnosis and potentially offer personalized treatment. They treated four individuals with GRIN2A null-related mental disorders with the known NMDA receptor co-agonist L-serine and observed improvements in their neuropsychiatric phenotype.
References:
- Hoehe MR, Morris-Rosendahl DJ. The role of genetics and genomics in clinical psychiatry. Dialogues Clin Neurosci. 2018 Sep;20(3):169-177. doi: 10.31887/DCNS.2018.20.3/mhoehe. PMID: 30581286; PMCID: PMC6296395.
- Lemke, J.R., Eoli, A., Krey, I. et al. GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03279-4
