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Schizophrenia affects 1% of the general population at some stage of their lives, but that figure increases to 10% in individuals who have a close relative with the disorder, such as a parent or sibling. And if you have an identical twin with this mental illness, you have up to a 65% chance of developing it yourself. Needless to say, genetics clearly plays a role in its origins, but scientists have struggled to pinpoint which genes could be responsible for the disease.

Now, after conducting the largest study of its kind, scientists believe they have gathered the most convincing evidence of the DNA alterations that make things go awry in the brain, ultimately leading to the onset of schizophrenia. As described in the journal Neuron, researchers found that a number of schizophrenia-associated gene variations can disrupt the brain’s fragile chemical balance.

The genes in question are involved in preventing neurons from firing out excessive amounts of chemical messengers after stimulation, and thus contribute to inhibitory signaling in the brain. The researchers believe that these mutations therefore allow regions of the brain to become excessively excited, which can be detrimental to cell health if not corrected.

“We’re finally starting to understand what goes wrong in schizophrenia,” lead author Dr. Andrew Pocklington said in a statement. “We now have what we hope is a pretty sizeable piece of the jigsaw puzzle that will help us develop a coherent model of the disease, while helping us to rule out some of the alternatives.”

This research, conducted at Cardiff University, actually builds on prior research by members of the same team that hinted that mutations associated with this mental illness could be interfering with so-called excitatory chemical signaling in the brain. While brain cells need to possess the ability to become excited and fire signals to one another in order to transmit information, there also needs to be a counter system to prevent them from over-firing and ultimately causing cellular damage. This delicate balance of excitatory and inhibitory signaling is therefore pivotal to proper brain functioning.

Although these earlier findings led to the publication of two landmark studies in the prestigious journal Nature, the team now has even more evidence to support the idea that disruption of excitatory signaling in the brain contributes to schizophrenia, rather than being a secondary effect of the disease.

For the investigation, researchers obtained and analyzed genetic data collected from 11,355 schizophrenic patients and 16,416 people without the disorder. More specifically, they were looking for copy number variants (CNVs) within their DNA, which are deletions or gains of large chunks of sequences that result in cells having an abnormal number of copies of certain stretches of DNA.

By comparing CNVs between the two groups, the researchers found that schizophrenic individuals tended to have variations in genes involved in the transmission of a chemical messenger called GABA, which is a major inhibitory neurotransmitter in the brain.

Furthermore, confirming their previous work, they also found that genes involved in the brain’s major excitatory system, mediated by the neurotransmitter glutamate, are also enriched with CNVs in people with schizophrenia. Since the GABA signaling system has strong functional links with the brain’s major excitatory system, their findings strongly indicate that a disruption of inhibitory signaling plays a role in schizophrenia. The researchers therefore conclude that faulty GABA signaling is a cause, rather than an effect, of schizophrenia. 

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