Schizophrenia: Global Study Identifies Key Genes Of The Disease
- Lidi Garcia
- Sep 16
- 4 min read
Schizophrenia is a serious mental disorder strongly linked to genetics. Rather than being caused by a single gene, it results from the combination of many different DNA variations, some very common and others quite rare. Recent studies analyzing thousands of people have identified genes linked to neuron communication and DNA organization that increase the risk of the disease. These discoveries help scientists better understand the biology of schizophrenia and may pave the way for new treatments in the future.
Schizophrenia is a serious and complex psychiatric disorder. It does not manifest itself the same way in everyone, but it generally causes changes in behavior, thinking, and the way a person perceives the world around them. Many patients live with symptoms that can last a lifetime, and currently available medications, called antipsychotics, are not always able to resolve all problems.
Research shows that schizophrenia has a strong link to genetic factors. This means that there isn't a single gene responsible, but rather thousands of small variations scattered throughout the DNA that, combined, increase a person's likelihood of developing the disease.
These common variations, which occur in a significant portion of the population, already explain a considerable portion of the risk of schizophrenia. Very large studies, involving tens of thousands of people, have already identified nearly three hundred regions in the human genome associated with the disease.
But it's not just common variations that matter. There are also rarer genetic alterations, which appear in very few people but can have a much greater impact on the risk of schizophrenia. Some of these rare alterations involve "breaks" or "losses" in pieces of DNA, which can include multiple genes at once.
Others involve specific mutations that disrupt the normal functioning of certain proteins essential to the brain. A well-established example is the NRXN1 gene, which is involved in communication between neurons.
Recent research has shown that many of these rare genetic alterations affect genes linked to fundamental brain functions, such as communication between neurons through the chemical glutamate and the regulation of which genes are active or inactive at any given time. These types of discoveries are important because they help scientists better understand the biological mechanisms that may underlie schizophrenia.
A massive international effort called SCHEMA, which gathered genetic data from tens of thousands of people with schizophrenia and volunteers without the disease, identified a small group of genes that appear to have a very strong link with the disorder.
These genes not only increase the risk of schizophrenia but also appear in other developmental problems, such as intellectual disability. This suggests that some of the biology of schizophrenia overlaps with other neurological and psychiatric disorders. Such as the genes STAG1, SLC6A1, ZMYND11, and CGREF1, which have previously been associated with autism, epilepsy, and developmental delay.
In the most recent study, scientists conducted the largest analysis ever conducted of the exome, which is the part of DNA that contains the instructions for making proteins. They examined nearly thirty thousand people with schizophrenia and more than one hundred thousand people without the disease. Using this enormous database, they were able to confirm the importance of some already known genes and, at the same time, discover new candidates related to schizophrenia risk.
The genes identified were:
STAG1: is linked to chromatin organization, which is how DNA is coiled and stored within the cell. If this process doesn't work properly, it can disrupt the control of which genes are turned on or off.
ZNF136: is a gene that helps control the activity of other genes. If there are defects, this can affect important processes in the brain.
SLC6A1: related to the transport of the neurotransmitter GABA, which helps calm the activity of neurons. Alterations here can cause imbalances between excitation and inhibition in the brain.
PCLO: participates in communication between neurons at synapses, the points of contact where messages pass in the brain.
ZMYND11: helps control how genes are read and used. Problems with this gene can impact various brain functions.
BSCL2: important for the structure and health of neurons.
KLC1: acts in the transport of proteins within nerve cells, essential for keeping neurons functioning properly.
CGREF1: Participates in cell growth and survival processes.
These include genes linked to the transport of chemicals in the brain, the organization of chromatin (the structure that surrounds and organizes DNA within cells), and other processes essential for communication between neurons and the control of which genes are active. When something goes wrong in one or more of these areas, it can contribute to the risk of developing schizophrenia.
These findings reinforce the idea that schizophrenia doesn't have a single cause, but rather results from the combination of many different genetic alterations, each contributing a small or large effect.
By mapping these genes and their functions, scientists are beginning to paint a more detailed picture of the neurobiology of the disease. This paves the way for the development of new, more precise and targeted treatments in the future, which can act on the biological roots of the disorder, not just the symptoms.
READ MORE:
Whole-exome sequencing analysis identifies risk genes for schizophrenia
Sophie L. Chick, Peter Holmans, Darren Cameron, Detelina Grozeva, Rebecca Sims, Julie Williams, Nicholas J. Bray, Michael J. Owen, Michael C. O’Donovan, James T. R. Walters, and Elliott Rees
Nature Communications, volume 16, Article number: 7102 (2025)
Abstract:
Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 genes at exome-wide levels of significance. To increase power for gene discovery, we analyse exome-sequencing data for rare coding variants in a new sample of 4650 schizophrenia cases and 5719 controls, and combine these with published sequencing data for a total of 28,898 cases, 103,041 controls and 3444 proband-parent trios. We identify associations for STAG1 and ZNF136 at exome-wide significance, genes that were previously implicated in schizophrenia by the SCHEMA study at a false discovery rate of 5%. We also find associations at a false discovery rate of 5% for six genes that did not pass this statistical threshold in the SCHEMA study (SLC6A1, PCLO, ZMYND11, BSCL2, KLC1 and CGREF1). Among these genes, SLC6A1 and KLC1 are associated with damaging missense variants alone. STAG1, SLC6A1, ZMYND11 and CGREF1 are also enriched for rare coding variants in other developmental and psychiatric disorders. Moreover, STAG1 and KLC1 have fine-mapped common variant signals in schizophrenia. These findings provide insights into the neurobiology of schizophrenia, including further evidence suggesting an aetiological role for disrupted chromatin organisation.
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