Research Helps Show How a Specific Gene Mutation is Linked to Schizophrenia



Researchers with Columbia University in New York City published research showing how one of the genes that has definitely been tied to schizophrenia, SETD1A, works to increase risk of the disease.

Only a few genes have definitively been linked to schizophrenia. A mutant form of the SETD1A gene clearly confers risk for the disease. Other genetic variations associated with schizophrenia only have slight effects, but a single mutant copy of SETD1A is associated with a large increase in disease risk. The gene plays a key role in epigenomic regulation, turning on or off genes in response to experience, a process common in the brain.

But exactly how this process works wasn’t clearly understood. The researchers, led by Joseph Gogos, published their findings in the journal Neuron.

“You could call SETD1A a master regulator,” said David Panchison, of the National Institute of Health (NIH)’s National Institute of Mental Health (NIMH), which co-funded the study. “This schizophrenia risk gene codes for an enzyme that influences the expression of many other genes. In mice, a hobbled version of SETD1A disrupted gene expression in a network harboring other genomic suspects in schizophrenia. Remarkably, the resulting abnormalities were reversible.”

The research team genetically engineered laboratory mice to knock out the SETD1A gene. The mice were then found to have problems with working memory, similar to what is seen in schizophrenia patients. Restoring the gene’s function fixed the memory issues. They also found that counteracting the deficiencies in the gene repaired the brain circuit problems in adult mice. This shows significant potential for treatment approaches.

The researchers wrote, “Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice.”

LSD1 is required for normal differentiation and maintenance of stem cells. Among other things, LSD1 is overexpressed in several types of cancer and is thought to promote tumors. It has been implicated in a variety of diseases and plays an important role in cell proliferation, chromosome segregation, embryonic development and the genesis of fat cells (adipogenesis) and sperm (spermatogenesis).

The mutated gene disrupted the way neurons communicate with each other. It affected the growth and branching of cell extensions and decreased the number of spikes on the extension. The nerve cell extensions deliver chemical signals from nearby cells.

“Although SETD1A mutations exist in a small percentage of all schizophrenia patients, many people diagnosed with the disorder have issues similar to those caused by this mutation,” said Gogos. “Thus, therapies that are specific to SETD1A may indeed have wider implications for schizophrenia as a whole.”

The original research into SETD1A linking it to schizophrenia was published in 2016. Researchers at Britain’s Wellcome Trust Sanger Institute found that mutations to the gene increase the risk of schizophrenia 35 times. It also increases the risk of other neurodevelopmental disorders.

The mutations found in SETD1A aren’t seen in all schizophrenia patients, in fact, are only seen in about 1 in 1,000 people with schizophrenia. However, the gene and these studies provide important information to the biology of the illness.

Schizophrenia affects about one in 100 people worldwide. It is a severe psychiatric illness including disruptive thinking, language and perception, as well as psychotic experiences.



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