The most comprehensive evidence to date of schizophrenia’s causes has been produced by an international team of scientists led by researchers at Cardiff University. The team uncovered that some mutations that increase the probability of the condition may interfere with the delicate chemical balance in the brain. The study, the largest of its kind, was published last week in the journal Neuron.
Schizophrenia is a mental condition that affects the way roughly 1 in 100 people think. At times, patients may experience hallucinations or unusual beliefs as well as demotivation and withdrawal. Many different factors are thought to influence the likelihood of developing schizophrenia and research labs are working tirelessly to investigate the specific causes.
Until now, the biology of schizophrenia has been somewhat mysterious; genetic studies are beginning to uncover some clues about the condition. “[Our] current study, the largest of its kind, confirms previous findings about the role of a type of neuronal signalling related to the chemical glutamate [and] extends this to reveal that signalling related to another neuro-transmitter, GABA, is involved,” Michael O’Donovan, Professor of Psychiatric Genetics at Cardiff University told The Positive. “Together, these two signalling molecules play important roles in how the strength of connections between nerve cells is regulated, a process important in learning and memory.”
The study is the most comprehensive of its kind analysing more than 27,000 samples. “We’re finally starting to understand what [happens] in schizophrenia,” says lead author Dr Andrew Pocklington. The team discovered mutations linked to schizophrenia may interfere with other genes involved in excitatory and inhibitory signalling in the brain, providing the first genetic evidence implicating disruption of nerve activity in the condition. The balance between these two types of neurones is necessary for healthy brain development and function.
In order to investigate the genetic underpinnings of the condition, researchers searched for a rare class of mutations known as copy number variants (CNVs). CNVs are mutations in the genome where large stretches of DNA are either duplicated or deleted. By comparing CNVs found in schizophrenia patients versus unaffected people, the team was able to produce novel proof that interference with GABAergic neurones (neurones that inhibit signalling) increases the likelihood of developing schizophrenia. The authors suggest that this initial mutation may spark an unknown chain reaction of sub cellular events in the brain.
The Cardiff team have also been looking at single nucleotide polymorphisms (SNPs), pronounced “snips”, to provide an insight into schizophrenia, publishing a significant study in Nature last year. A SNP is a single base change in DNA. For example, two DNA fragments from different individuals, AAGCCTA and AAGCTTA, contain a difference in a single nucleotide, known as a SNP. Their abundance throughout the genome makes them an excellent tool for research.
“We have found before that rare mutations sometimes [may] provide a clearer insight than SNPs, although as our SNP studies get better and better (and bigger and bigger), that may change. So short answer – we are doing both.”
The effects of the CNVs uncovered in this study are also suspected to be involved in other conditions such as Autism and ADHD. “The approaches we take here are likely applicable to many other disorders. [And] so are the findings. Although the specific findings have to be tested in other conditions, we already know that schizophrenia has partly shared genetics with autism, intellectual disability, ADHD and epilepsy,” said O’Donovan to The Positive.
According to O’Donovan, “[the] research is part of a medium-term endeavour. We hope that by unmasking the hidden biology (or more likely, biologies) of the disorder, it [might] become possible to identify new ways of developing treatments.” The team’s efforts succeed in bringing science closer to the clinic, however there are still many mysteries to be solved to gain a more comprehensive view of the condition. Nevertheless, it represents a sizeable piece of the biological jigsaw puzzle for schizophrenia and may direct new treatments for the condition. In addition, the team are also investigating how CNVs might be used clinically for testing in people with schizophrenia.
How might these findings be applicable to other mental health conditions?