Scientists have discovered 287 regions of the human genome that contribute to the genetic risk of developing schizophrenia. It is the culmination work by researchers from 45 countries and the participation of more than 300,000 people.
Researchers in Trinity College Dublin led by Prof Aiden Corvin examined data from 2,000 Irish patients and contributed to two related studies published on Wednesday in Nature.
Schizophrenia is a serious psychiatric disorder that starts in late adolescence or early adulthood and at any one time affects around one in 300 people – almost 1 per cent of the adult population. Current treatments are only partially effective, reflecting limited understanding of the biology involved, which has frustrated efforts to develop better treatments.
The first study led by the Psychiatric Genomics Consortium (PGC), was an investigation of almost 70,000 patients and 240,000 people who did not have the condition.
It identified 287 genomic regions that have subtle, small effects on schizophrenia risk across the population. They were concentrated in genes expressed in the central nervous system, which includes the brain.
The study “not only vastly increases the number of these associations, but provides tighter links to specific genes, rather than broader regions, representing a key step on our journey of discovery”, explained Prof Corvin of TCD Psychiatric Research Group.
Director of the Galway Neuroscience Centre at NUI Galway, Dr Derek Morris, formerly of TCD, said: "Although there are large numbers of genetic variants involved in schizophrenia, the study showed they are concentrated in genes expressed in neurons, pointing to these cells as the most important site of pathology."
Diverse symptoms
The findings suggest abnormal neuron function in schizophrenia affects many brain areas, which could explain its diverse symptoms such as hallucinations, delusions and problems with thinking clearly.
The second study led by scientists in Harvard University and MIT in the US took a different approach to provide a clearer view of the molecular mechanisms likely to be responsible.
It focused on extremely rare protein-disrupting mutations that significantly increase an individual’s risk of developing schizophrenia and identified 10 such genes - in one instance, increasing risk by more than 20-fold.
Dr Joshua Gordon, director of National Institute of Mental Health (NIMH) in the US said: "These results, achieved through a global collaboration unprecedented in scope, mark an important step forward in our understanding of the origins of schizophrenia. The findings will allow researchers to focus on specific brain pathways in the ongoing hunt for novel therapies."
Both studies underline the importance of regulation of “the synaptic function” – the transmission of nerve impulses between two nerve cells (neurons) – across the brain in development of schizophrenia. However, they note other mechanisms involving how genes are transcribed and old proteins are recycled are also likely to be involved in this complex condition.
The second study identified a spectrum of risk where more damaging mutations in the genes were associated with more adverse consequences and more severe disorders. This offers hope that biological insights from this work will have wider implications across brain disorders.
Prof Corvin added: “More than 3,000 Irish people have participated in our gene discovery programme over more than 20 years. We realised early on that only large scale collaborations would yield the kind of power needed to make real breakthroughs.”
While people with schizophrenia can recover, many do not respond well to treatments, experience long-term problems with their mental and physical health, as well as impacts on relationships, education and work, said Prof James Walters, co-lead author of the PGC paper and director of the Centre for Neuropsychiatric Genetics and Genomics at Cardiff University.
“We hope the findings...can be used to advance our understanding of the disorder and facilitate the development of radically new treatments. However, those processes are often not straightforward, and a lot of work by other neuroscientists is needed to translate the genetic findings into a detailed understanding of disease mechanisms,” he added.
Scientists at TCD and NUIG, funded by Science Foundation Ireland and the NIMH, are building on this work to develop more detailed datasets and to explore more the molecular mechanisms involved.
