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New light shed on biology underlying schizophrenia

Genes and pathways identified by the international study could inform new approaches to treatment

by HSC staff
Researchers Carlos and Michele Pato
Keck Medicine of USC psychiatrists Carlos and Michele Pato are co-authors on the largest genomic study published on any psychiatric disorder to date. (USC Photo/Philip Channing)

Keck Medicine of USC researchers, as part of a multinational effort, have helped identify more than 100 locations in the human genome associated with the risk of developing schizophrenia.

In what is the largest genomic study published on any psychiatric disorder to date, the findings, which are published online in Nature, point to biological mechanisms and pathways that may underlie schizophrenia. These pathways could lead to new approaches to treating the disorder, which has seen little innovation in drug development in more than 60 years.

The enormous cost of schizophrenia

Schizophrenia, a debilitating psychiatric disorder that affects approximately one out of every 100 people worldwide, is characterized by hallucinations, paranoia and a breakdown of thought processes, and often emerges in the teens and early 20s. Its lifetime impact on individuals, their families and society is high, both in terms of health and financial cost. Studies estimate the cost of schizophrenia at more than $60 billion annually in the United States alone, based on individuals’ inability to maintain steady employment, medication expenses and other treatment.

The Genomic Psychiatry Cohort studies, led by Keck Medicine of USC psychiatrists Carlos and Michele Pato, have enrolled 33,000 participants with schizophrenia, bipolar disorder or who are unaffected control participants.

Despite the pressing need for treatment, medications currently on the market treat only one of the symptoms of the disorder (psychosis) and do not address the debilitating cognitive symptoms of schizophrenia. In part, treatment options are limited because the biological mechanisms underlying schizophrenia have not been understood. The sole drug target for existing treatments was found serendipitously, and no medications with fundamentally new mechanisms of action have been developed since the 1950s.

In the genomics era, research has focused on the genetic underpinnings of schizophrenia because of the disorder’s high heritability. Previous studies have revealed the complexity of the disease (with evidence suggesting that it is caused by the combined effects of many genes), and roughly two dozen genomic regions have been found to be associated with the disorder. The new study confirms those earlier findings and expands our understanding of the genetic basis of schizophrenia and its underlying biology.

“By studying the genome, we are getting a better handle on the genetic variations that are making people vulnerable to psychiatric disease,” said Tom Insel, director of the National Institute of Mental Health (NIMH), which helped fund the study. “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.”

In the genome-wide association study published in Nature, the authors looked at more than 80,000 genetic samples from schizophrenia patients and healthy volunteers and found 108 specific locations in the human genome associated with risk for schizophrenia. Eighty-three of those loci had not previously been linked to the disorder.

“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,” said first author Stephan Ripke, a scientist at the Broad’s Stanley Center for Psychiatric Research and the Analytical and Translational Genetics Unit at Massachusetts General Hospital. “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.”

Active genes in the immune system

The study implicates genes expressed in brain tissue, particularly those related to neuronal and synaptic function. These include genes that are active in pathways controlling synaptic plasticity — a function essential to learning and memory — and pathways governing postsynaptic activity, such as voltage-gated calcium channels, which are involved in signaling between cells in the brain.

The researchers also found a smaller number of genes associated with schizophrenia that are active in the immune system, a discovery that offers some support for a previously hypothesized link between schizophrenia and immunological processes. In addition, the study found an association between the disorder and the region of the genome that holds DRD2 — the gene that produces the dopamine receptor targeted by all approved medications for schizophrenia — suggesting that other loci uncovered in the study may point to additional therapeutic targets.

“The fact that we were able to detect genetic risk factors on this massive scale shows that schizophrenia can be tackled by the same approaches that have already transformed our understanding of other diseases,” said the paper’s senior author Michael O’Donovan, deputy director of the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University’s School of Medicine. “The wealth of new findings have the potential to kick-start the development of new treatments in schizophrenia, a process which has stalled for the last 60 years.”

Taking the next step

The study is the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium, an international, multi-institutional collaboration founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease. One-third of the samples used in the study were genotyped at the Broad Institute, but a total of 55 datasets from more than 40 different contributors were needed to conduct the analysis.

“A vital next step is the planned genome-wide SNP genotyping and whole genome sequencing of greater than 20,000 additional subjects through the Genomic Psychiatry Cohort at USC, in partnership with the Broad Institute and the University of Michigan,” said co-author Carlos Pato, professor and chair of the Department of Psychiatry and the Behavioral Sciences at the Keck School of Medicine of USC.

The Genomic Psychiatry Cohort studies, led by Keck Medicine of USC psychiatrists Pato and Michele Pato, have enrolled 33,000 participants with schizophrenia, bipolar disorder or who are unaffected control participants, through 12 participating institutions nationally, with plans to add more than 17,000 additional participants over the next five years.

Core funding for the Psychiatric Genomics Consortium comes from the NIMH, along with numerous grants from governmental and charitable organizations, as well as philanthropic donations. Work conducted at the Stanley Center for Psychiatric Research was funded by the Stanley Medical Research Institute, Merck Research Laboratories, the Herman Foundation and philanthropic donations. The Genomic Psychiatry Cohort at USC has been funded by multiple NIMH grants.

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