International team sheds new light on biology underlying schizophrenia - Applied Clinical Trials

ADVERTISEMENT

See our 2013 Buyers Guide Digital Edition.
International team sheds new light on biology underlying schizophrenia Genes, pathways identified could inform new approaches to treatment


International team sheds new light on biology underlying schizophrenia

Genes, pathways identified could inform new approaches to treatment

PR Newswire

CAMBRIDGE, Mass., July 21, 2014 /PRNewswire/ -- As part of a multinational, collaborative effort, researchers from the Broad Institute, Massachusetts General Hospital (MGH), and scores of other institutions from all over the world have helped identify over 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, and could lead to new approaches to treating the disorder, which has seen little innovation in drug development in more than 60 years.

Broad Institute Logo

Schizophrenia, a debilitating psychiatric disorder that affects approximately 1 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 and society is high, both in terms of years of healthy life lost to disability and in terms of financial cost, with studies estimating the cost of schizophrenia at over $60 billion annually in the U.S. alone.

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, 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 (GWAS) published in Nature, the authors looked at over 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 MGH. "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."

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.

Additionally, the researchers 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. The study also 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 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."

The study is the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC, http://pgc.unc.edu), 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.

"This level of cooperation between institutions is absolutely essential," said Steve Hyman, director of the Broad's Stanley Center for Psychiatric Research and Distinguished Service Professor of Stem Cell and Regenerative Biology at Harvard University. "Because of the genetic complexity of schizophrenia and other psychiatric disorders, we need a large sample size to conduct this type of research.  If we are to continue elucidating the biology of psychiatric disease through genomic research, we must continue to work together."

The 80,000 samples used in this study represent all of the genotyped datasets for schizophrenia that the consortium has amassed to date. The PGC is currently genotyping new samples to further study schizophrenia and additional psychiatric diseases, including autism and bipolar disorder.   

Core funding for the Psychiatric Genomics Consortium comes from the U.S. National Institute of Mental Health (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.

Paper cited:

Schizophrenia Working Group of the Psychiatric Genomics Consortium. "Biological insights from 108 schizophrenia-associated genetic loci." Nature. July 22, 2014. DOI: 10.1038/nature13595.

About GWAS
Genome-wide association studies (GWAS) examine the frequency of common variations within the human genome to determine which locations in the genome may be linked to a specific phenotype, or trait (usually, a disease). To study these variations, researchers scan strategically selected sites of the genome that are known to vary considerably across the population, taking note of single nucleotide polymorphisms (SNPs) – single-letter variations in the genetic code. SNPs found to be significantly more common in people with a trait than in those without are considered to be "associated" with that phenotype. Where the associated SNP resides in the genome can provide valuable clues about the genes and mechanisms that may be contributing to the phenotype being studied.

About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.

Logo - http://photos.prnewswire.com/prnh/20140520/89735

SOURCE Broad Institute

ADVERTISEMENT

blog comments powered by Disqus

ADVERTISEMENT

UPCOMING CONFERENCES

8th Annual Forum on Transparency and Aggregate Spend 2014
Washington, DC
August 18-20, 2014

eSource Data in Clinical Investigations
Philadelphia, PA
August 20-21, 2014

Pharmacovigilance 2014
Philadelphia, PA
September 10-11, 2014

Collaborative Research Summit
Philadelphia, PA
October 15-16, 2014

See All Conferences >>

Survey
As it creates a plan to implement the US biosimilar pathway, should FDA:
Borrow heavily from EMA's pathway program?
Borrow lightly from EMA's pathway program?
Create entirely its own pathway program?
Borrow heavily from EMA's pathway program?
86%
Borrow lightly from EMA's pathway program?
6%
Create entirely its own pathway program?
7%
View Results
Untitled Document

Click here