De Novo Gene Mutations Linked to Schizophrenia

Megan Brooks

January 27, 2014

De novo genetic mutations in individuals with schizophrenia cluster in specific proteins that play a key role in brain function and overlap with mutations seen in autism, an international team of scientists report.

Although inherited genetic mutations account for most of the genetic risk for schizophrenia, emerging evidence shows that uninherited (de novo) mutations also are involved.

The latest evidence, reported online January 22 in 2 articles in Nature, comes from leading research teams in the United States and Europe.

In one study, co-led by Michael J. Owen, MD, PhD, and Professor Michael C. O'Donovan from Cardiff University's Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, scientists used exome sequencing to search for de novo mutations in 623 patients with schizophrenia and their parents.

The team found that mutations in genes involved in synaptic pathways were overrepresented in the patients with schizophrenia but not in their parents.

These pathways are involved in modulating the strength of connections between nerve cells, suggesting that dysfunction in these pathways is one mechanism by which schizophrenia may develop.

Mutations in genes that control proteins that interact with the fragile X mental retardation protein were also more common in the schizophrenia patients. The researchers also identified gene mutations in the schizophrenia patients that overlap with those mutated in autism and intellectual disability.

On the Way to Better Treatment

In a second study, Shaun Purcell, PhD, of the Broad Institute of the Massachusetts Institute of Technology in Cambridge, and colleagues analyzed the exome sequences of 2536 individuals with schizophrenia and 2543 control participants.

In that research, the investigators found evidence that rare, disruptive mutations distributed across many genes increase the risk for schizophrenia. Included in these genes are those related to calcium channels and synaptic machinery, supporting the work from Cardiff. Dr. Purcell's team also found mutations in targets of the fragile X mental retardation protein, which is also observed in autism.

Dr. Owen told Medscape Medical News that there are now several articles "implicating these postsynaptic gene sets in schizophrenia. This level of convergence is striking and unusual in schizophrenia genetics," he said.

"The fact we've been able to identify a degree of overlap between the underlying causes of schizophrenia and those in autism and intellectual disability suggests that these disorders might share some common mechanisms and lends further weight to calls for research that integrates findings across multiple disorders," Dr. O'Donovan added in a statement.

"Our plans are next to study these genes in more detail and in greater numbers of sufferers in order to try and estimate how big a contribution they make in the population. Second, we are starting a major program seeking to understand how the mutations impact on brain function, both on the development of the brain and on its function, particularly synaptic plasticity," said Dr. Owen.

"There are no clinical implications right now, but we hope these new studies will be the next step on the way to better treatments," he added.

"Understanding how our genetic code contributes to schizophrenia is crucial if we are to develop better, safer treatments," Professor Hugh Perry, chair of the MRC Neurosciences and Mental Health Board, said in a statement.

"Such advances in developmental biology will help us to unravel the complexity of emotional and behavioral disturbances," he added.

The studies had no commercial funding. The original articles contain complete lists of funding agencies and author disclosures.

Nature. Published online January 22, 2014. Abstract, Abstract

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