As part of a multinational, collaborative study, researchers from the School of Medicine in Trinity College Dublin have helped to 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 have just been published online in Nature today, point to biological mechanisms and pathways that may underlie schizophrenia. This could lead to new approaches to treating the disorder which has seen little innovation in drug development in more than 60 years.
Schizophrenia is a debilitating psychiatric disorder that affects approximately 1 out of every 100 people in Ireland and worldwide. It is characterized by hallucinations, delusions, and impaired social function, and often emerges in the teens and early 20s. Its lifetime impact on individuals, families and society is high, both in terms of years of healthy life lost to disability, reduced life expectancy and financial cost.
Previous studies have revealed the complexity of the disease (with evidence suggesting that it is caused by the combined effects of many genes), and approximately 20 genomic regions were found to be associated with the disorder. This new study confirms those earlier findings, and substantially expands our understanding of the genetic basis of schizophrenia and its underlying biology.
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, including over 3,500 Irish participants, 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 genomics, collaboration is key. This study is transformative, in showing that we can systematically identify many genetic risk factors for schizophrenia using approaches that have been successful for other diseases,” said Aiden Corvin, Professor of Psychiatry, School of Medicine, Trinity College Dublin and Head of the Psychosis Research Group at Trinity who was one of the lead authors of the study.
Professor Corvin continued: “Now that we have more pieces of the puzzle, we are starting to group genes into identifiable pathways so that we can explore schizophrenia at a biological level.”
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 regions uncovered in the study may point to additional therapeutic targets.
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.
Michael O’Donovan, deputy director of the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University School of Medicine and the paper’s senior author said: ‘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.”
Professor Mark Ferguson, Director General of Science Foundation Ireland and Chief Scientific Adviser to the Irish Government said, “The results of this study demonstrate the benefit of collaboration across the international scientific ecosystem. SFI is committed to supporting the participation of Irish researchers in such projects, which can deliver demonstrable and significant societal and economic impact. Congratulations to all involved at Trinity College Dublin on this discovery which could be a major step forward in the diagnosis and treatment of psychiatric disorders.”
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. Almost 3,500 Irish participants made a substantial contribution to this study, but a total of 55 datasets from more than 40 different contributors were needed to conduct the analysis. 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 TCD Psychosis Research Group was funded by Science Foundation Ireland, the Health Research Board, the NIMH and the Wellcome Trust.
The full paper is available here: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13595.html
The paper’s full title is : Schizophrenia Working Group of the Psychiatric Genomics Consortium. “Biological insights from 108 schizophrenia-associated genetic loci.” Nature. DOI: 10.1038/nature13595.