As a rule, mental health disorders like schizophrenia are thought to be influenced by hundreds, perhaps thousands, of interacting genetic variants. The National Health Service (NHS), the healthcare system in the UK, said research suggests a combination of physical, genetic, psychological and environmental factors can increase the likelihood of developing schizophrenia. Some people may be prone to schizophrenia. For instance, in identical twins if a twin developed schizophrenia, the other twin has a 1 in 2 chance of developing it as well, even if they’re raised separately. But a new study suggests changes to the GRIN2A gene are associated with early-onset schizophrenia in childhood or early adolescence, much sooner than the disorder typically presents.
Molecular Psychiatry published a study by Lemke et al that found null variants of the GRIN2A gene (GRIN2Anull) were significantly associated with a broad spectrum of mental disorders, including schizophrenia, when compared to a longitudinal population cohort. This is a research study that tracks a large, defined group of people from a general population over a long time. The researchers used a registry of the world’s largest cohort of GRIN2A patients to investigate the effects of mutations in GRIN2A. The lead author of the study told ScienceAlert, “Our current findings indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness.”
The research found that GRIN2Anull carriers were at an elevated risk at a much younger age than the global population average. “The average age of onset for GRIN2Anull-related mental disorders was childhood or adolescence.” The elevated mental disorder risk of GRIN2Anull carriers not only included schizophrenia, but other mental disorders such as anxiety disorders. Unexpectedly, some participants in the study only showed psychiatric symptoms, even though GRIN2A changes are often linked to epilepsy or intellectual disability. I’m not sure this proves the GRIN2A gene “causes” schizophrenia any more than it “causes” epilepsy.
GRIN2A has initially been associated with neurodevelopmental disorders, comprising particularly developmental and epileptic encephalopathy, ID and speech disorders. Our findings indicate that mental disorders are not just one of many features of a complex neurodevelopmental phenotype of GRIN2Anull-related disorder but can be a leading clinical presentation rather than a co-morbidity or concomitant feature of epilepsy. Given the same prevalence of epilepsy among individuals with GRIN2Anull and GRIN2Amissense, we conclude that the presence of mental disorders among individuals with GRIN2Anull cannot easily considered to be a consequence or concomitant symptom of the diagnosis of epilepsy. In about half the individuals affected by epilepsy as well as mental disorders, the mental disorder started after the offset of epilepsy. However, it currently remains unclear whether the correlation between offset of epilepsy and onset of mental disorders has a biological cause.
The International Society of Psychiatric Genetics does not currently recommend genetic testing in the diagnostic work-up of isolated mental diseases, but the researchers suggested genetic testing should be considered to improve “diagnosis and potentially offer personalized treatment.” The marked heterogeneity of mental disorders has overshadowed the identification of monogenic, single gene entities. “Thus, our findings establish GRIN2Anull as the first monogenic predisposition to a broad spectrum of early-onset mental disorders, including early-onset schizophrenia.” But genetics is only one factor in the cause of schizophrenia.
The National Health Service said the exact causes of schizophrenia are not known. But research suggests a combination of physical, genetic, psychological and environmental factors can make a person more likely to develop the condition. In addition to genetics, differences in brain chemistry and structure, as well as environmental and developmental factors, and substance use (cannabis and stimulants like cocaine and amphetamines) can increase a person’s vulnerability. Traumatic, or major life stressors such as losing your job or home; physical, sexual, or emotional abuse; or bereavement can also trigger an initial psychotic episode in vulnerable individuals.
No Genetic Test Was Found
In March of 2024 E. Fuller Torrey, a psychiatrist and researcher on schizophrenia and bipolar disorder, wrote an article in Psychiatry Research, titled: “Did the human genome project affect research on Schizophrenia?” Torrey noted that schizophrenia was targeted by the Human Genome Project because three of its principle architects had a personal interest “and also because, based on family, adoption, and twin studies, schizophrenia was widely believed to be a genetic disorder.” He said extensive studies using various methods failed to identify causal genes. They did, however, identify almost 300 single nucleotide polymorphisms (SNPs) associated with altered risks of developing schizophrenia.
Risk genes play a role in the clinical expression of most diseases but do not cause the disease in the absence of other factors. Increasingly, observers question whether schizophrenia is strictly a genetic disorder. Beginning in 1996 NIMH began shifting its research resources from clinical studies to basic research based on the promise of the Human Genome Project. Consequently, three decades later NIMH’s genetics investment has yielded almost nothing clinically useful for individuals currently affected. It is time to review NIMH`s schizophrenia research portfolio.
From the earliest days of the Human Genome Project, researchers utilized the newly available technology to search for the putative genetic causes of psychiatric diseases. Every few months during the subsequent thirty plus years the media has announced a “major breakthrough” psychiatric genetic finding which was subsequently not replicated. This cycle of hypomanic enthusiasm followed by depression after a failure to replicate is similar to the clinical course of bipolar disorder itself.
In “Searching for the ‘Psychiatric Yeti’: Schizophrenia is Not Genetic,” Peter Simons examined and assessed the Torrey article and remarked it was surprising since Torrey has argued in the past that schizophrenia is a brain disease and should be treated medically. Yet, Torrey thought the decades-long attempt to locate the genetic basis for schizophrenia has failed. Simons said:
But the promised gains never materialized. The Human Genome Project did help in our understanding of other conditions, especially cancer, as well as the single-gene disorders. But for psychiatric disorders, no genetic test was found; no biological test was found; no psychiatric drug was developed based on a genetic discovery. Not for depression, anxiety, psychosis, bipolar disorder, OCD, ADHD, or any other “mental illness.”
Torrey concluded his article by noting while the human genome project hoped to discover the genetic causes, and ultimately better treatments for many diseases including schizophrenia, “Not a single gene has been found that can be causally linked to schizophrenia and the research has produced no improvements in treatments.” Now there is some research linking the GRIN2A gene to mental health conditions that include schizophrenia.
The research of Lemke et al with the GRIN2A gene is interesting, but not conclusive. It needs to be replicated by more than one other group of researchers and I’d like to suggest that E. Fuller Torrey lead one of the groups of researchers. He’s the Associate Director of Research of The Stanley Medical Research Institute, which has supported more than $550 million in research in over 30 countries since it began in 1989. Given the article he wrote for Psychiatry Research and the conclusion of his article, I think he would have the research expertise and needed objectivity for the task. For more on schizophrenia and genetics, see “The Quest for the Genetic Basis of Schizophrenia.”
