New Schizophrenia Genes Identified

Megan Brooks

July 22, 2014

A multinational team of researchers has identified 83 new genes associated with schizophrenia and a variant in 1 gene that also increases the risk for bipolar disorder and alcoholism.

The findings are reported in 2 separate articles ― one published online July 22 in Nature, the other published online July 18 in Psychiatric Genetics.

In Nature, the Schizophrenia Working Group of the Psychiatric Genomics Consortium reports a genome-wide association study of 36,989 adults with schizophrenia and 113,075 healthy adults. They identified 108 different genetic locations associated with the disease, 83 of which have not been previously reported.

In the journal Psychiatric Genetics, researchers from the United Kingdom report a genetic analysis of 4971 people with schizophrenia, bipolar disorder, or alcoholism and 1309 healthy control individuals.

They found that people with a variant in the metabotropic glutamate receptor 3 (GRM3) gene have a 2- to 3-fold increased risk of developing schizophrenia or alcohol dependence and about a 3-fold increased risk of developing bipolar disorder.

Next Big Drug Target?

The GRM3 gene is thought to be important in brain signaling, and the implicated variant is found in roughly 1 in 200 people.

"It may be that this variant could represent a very nonspecific risk factor for mental disorder in general," David Curtis, MD, PhD, FRCPsych, from University College London in the United Kingdom, and coauthor on both articles, told Medscape Medical News.

"We could be looking at the next big drug target for treating mental illness," he added in a statement.

"Immediately," said Dr. Curtis, "we could test for this GRM3 variant alongside testing for CNVs [copy number variants] and could give some people with schizophrenia some kind of explanation of why they had the illness ― that they had an abnormality of their genetic code which stopped this receptor working properly."

"Longer term," Dr. Curtis said, "it should help us understand what goes wrong in schizophrenia and assist us in developing new and better treatments. An obvious place to start would be to seek to develop pharmacologically active compounds which target this receptor (ie, mGluR2/3 agonists)."

This latest research implicates both glutamate transmission and calcium channels in schizophrenia development, the researchers note.

"Drug treatments for schizophrenia have barely changed over the past few decades, as they still target dopamine receptors," coauthor Andrew McQuillin, PhD, head of the UCL Molecular Psychiatry team that first discovered GRM3, notes in a statement.

"Schizophrenia treatments targeting glutamate receptors have been tested in the past without success. However, they might be more effective at treating patient groups with mutations in glutamate receptors such as GRM3," Dr. McQuillin said. "Overall, I expect we will see increased interest in drugs against both glutamate receptors and calcium channels as a result of the research," he added.

Wonders of Genomics

"By studying the genome, we are getting a better handle on the genetic variations that are making people vulnerable to psychiatric disease," Thomas Insel, MD, director of the National Institute of Mental Health (NIMH), noted in a statement from the Broad Institute at Massachusetts General Hospital, which is involved in the consortium. "Through the wonders of genomic technology, we are in a period in which, for the first time, we are beginning to understand many of the players at the molecular and cellular level," he added.

"In just a few short years, by analyzing tens of thousands of samples, our consortium has moved from identifying only a handful of loci associated with schizophrenia to finding so many that we can see patterns among them. We can group them into identifiable pathways ― which genes are known to work together to perform specific functions in the brain. This is helping us to understand the biology of schizophrenia," said Stephan Ripke, MD, of the Broad Institute's Stanley Center for Psychiatric Research.

Core funding for the Psychiatric Genomics Consortium is provided by the NIMH. Funding is also provided through numerous grants from governmental and charitable organizations, as well as philanthropic donations. A complete list of author disclosures is available with the online articles.

Nature. Published online July 22, 2014. Abstract

Psychiatr Genet. Published online July 18, 2014. Abstract

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