A new technique gives insight into gene mechanisms of schizophrenia.
Schizophrenia is a disabling condition characterized by delusions, hallucinations, and other significant cognitive difficulties.
Affecting almost 1 percent of the population, more than 50 million people are estimated to have schizophrenia worldwide.
Studying and understanding the condition has proven troublesome; although some of the symptoms can be managed, there is no cure, and how the disease works on a cellular level is not understood.
Although schizophrenia holds many secrets, one aspect is well-known – there is a strong genetic component.
It often runs in families, and, for individuals with a first-degree relative with schizophrenia, the risk rises from 1 percent to 10 percent.
In 2014, a large-scale genome-wide association study of people with schizophrenia linked the disorder to small DNA changes in more than 100 locations in the genome.
Surprisingly, the majority of the altered portions were found to lay outside of the actual genes. This perplexed researchers; understanding what roles these snippets of code play in schizophrenia has been challenging.
Some of the non-gene locations identified in the studies were found to be in so-called regulatory regions. These sections of code repress or enhance the activity of certain genes that lie close to them within the genome.
However, many of these regulatory regions had no obvious gene targets near their location.
Schizophrenia’s secrets lie in the folds
Each cell has approximately 2 meters of DNA condensed into a nucleus just 6 micrometers across. This feat is the equivalent of packing 40 kilometers of thin thread into a tennis ball. When DNA is precisely packaged into a chromosome in this way, it is thoroughly twisted and looped. Researchers wondered whether, during these contortions, the schizophrenia-linked sections might come into close contact with distant genes.
Researchers from David Geffen School of Medicine at University of California-Los Angeles set out to understand if this was the case. Principal investigator Dr. Daniel Geschwind and his team used a state of the art, high-resolution version of a technology known as chromosome conformation capture.
Chromosome conformation capture chemically marks and then maps the points at which DNA comes in contact with itself as it folds. Each cell in the human body has subtly different ways of manipulating and packaging its DNA. So, the team decided to focus their search on immature human brain cells in the cortex.
They chose the cortex specifically because its abnormal cortical development is thought to be involved in schizophrenia.
The researchers found that the majority of the 100 disease-linked sites that had been previously found did indeed contact genes involved in brain development. Additionally, many of these new locations were already known to be involved in schizophrenia or had previously been shown to have increased levels of activity in schizophrenic brains.
Some of these newly pinpointed schizophrenia-related genes are activated by acetylcholine, a neurotransmitter thought to be at least partially involved in the development of schizophrenia.
“There’s a lot of clinical and pharmacologic data suggesting that changes in acetylcholine signaling in the brain can worsen schizophrenia symptoms, but until now there’s been no genetic evidence that it can help cause the disorder.”
Dr. Daniel Geschwind
In addition to the acetylcholinergic neurons, other genes that are known to be involved in the early development of the cerebral cortex were also implicated by the new technique.
A new approach for a variety of diseases
Overall, the study, published this week in Nature, identified hundreds of genes that might be abnormally regulated in a schizophrenic brain.
The study signals a new direction for schizophrenia research. Dr. Geschwind says: “This work provides a road map for understanding how common genetic variation associated with a complex disease affects specific genes and pathways.”
Before better treatment for schizophrenia can be designed, a stronger understanding of its etiology is needed. Innovative research such as this is an important stepping stone toward improvements in pharmacological interventions.
Because the present study used an original approach, it is also likely to assist in other areas of study. Dr. Geschwind says: “We’re also planning to apply this same strategy to identify key genes in the development of autism and other neurodevelopmental disorders.”