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Largest genetic study of schizophrenia points to new disease mechanisms

Posted on 22/07/2014
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As part of a multinational, collaborative effort, researchers from the Institute of Psychiatry at King’s College London have helped identify over 100 locations in the human genome associated with the risk of developing schizophrenia. With more than 80,000 genetic samples analysed, it is the largest genomic study published on any psychiatric disorder to date. 

Schizophrenia has seen little innovation in drug development in over 60 years.  These findings point to biological mechanisms and pathways that could underlie the disorder and may lead to new approaches to treatment. 

The study, published today in Nature, was co-authored by Professors Sir Robin Murray, John Powell and David Collier from King’s and was led by Cardiff University and Harvard Medical School. 

Schizophrenia affects approximately 1 out of every 100 people worldwide. It is characterized by hallucinations, paranoia, and a breakdown of thought processes which 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.  Research estimates the societal cost of schizophrenia to be £11.8 billion per year in England alone.  

There is a pressing need for more effective treatments. Current treatment options are limited, in part, 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.

Recent 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. This new study confirms these 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.”

“For many years, the architecture of the known genetic contribution to schizophrenia eluded us,” added Sir Robin Murray, Professor of Psychiatric Research in the Department of Psychosis Studies at the Institute of Psychiatry at King’s. “Now this huge collaborative effort has demonstrated that lots of genes of small effect contribute to this liability. This should open the door to measuring the extent of predisposition, and to understanding which particular pathways are involved. Ultimately this may help to split up the syndrome of schizophrenia and break it down into different conditions which respond to different treatments.” 

The genome-wide association study (GWAS) published today included over 80,000 genetic samples from people with schizophrenia and healthy volunteers. It found 108 specific locations in the human genome associated with risk of schizophrenia, 83 of which had not previously been linked to the disorder. 

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). Core funding for the PGC 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 reference: Schizophrenia Working Group of the Psychiatric Genomics Consortium. “Biological insights from 108 schizophrenia-associated genetic loci” published in Nature. DOI: 10.1038/nature13595. 

For further information, please contact Seil Collins, Press Officer, Institute of Psychiatry, King's College London seil.collins@kcl.ac.uk or (+44) 0207 848 5377

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