Over 280 regions of the genome that contribute to the genetic risk of developing schizophrenia have been identified by researchers working worldwide, including a team from Trinity College Dublin (TCD).

The regions of the genome were identified in two studies that involved over 300,000 people in more than 40 countries. The Irish data involved over 2,000 patients.

In the first study, the Psychiatric Genomics Consortium (PGC), of which TCD is a member, investigated almost 70,000 patients and 240,000 controls.

An analysis of genetic variants that are common in the population was carried out and this identified 287 genomic regions that have subtle, small effects on the risk of schizophrenia across the population.

These findings were concentrated in genes expressed in the central nervous system, particularly those implicated in synaptic organisation, differentiation, and transmission. 

“The present 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,” commented lead researcher for the Irish leg,  Prof Aiden Corvin, of TCD’s Psychiatric Research Group. 

These findings are significant because they explain a quarter of the genetic variance in schizophrenia susceptibility, representing a framework for further discovery. While most people will carry some of these variants, their individual contribution to risk is subtle, increasing risk from the general population level of about 1% to 1.2%.

“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.

“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,” noted Dr Derek Morris, formerly of TCD and now director of the Galway Neuroscience Centre at NUIG.

The second  study took a different approach in order to provide a clearer view of the molecular mechanisms likely to be responsible. It was coordinated by researchers at the Broad Institute of Harvard and MIT and published by the international SCHEMA Consortium, of which TCD is a member.

It focused on extremely rare protein-disrupting mutations that significantly increase an individual’s risk of developing schizophrenia. The work identified 10 such genes in one instance, increasing risk by more than 20-fold.

The mutations were individually rare (e.g. present in one in 1,000 cases) and were only confirmed because of the scale of the study, which involved genome sequencing of over 24,000 affected individuals. 

Significantly, both studies converged in identifying genes involved in the formation and maintenance of synapses between neurons, including those involved in the function of the glutamatergic neurotransmitter system. 

“These results, which were 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 for this serious mental illness,” commented Dr Joshua Gordon, director of the National Institute of Mental Health in the US.

When examined together, both studies show the importance of the regulation of synaptic function across the brain in the development of schizophrenia. The studies also highlighted that other mechanisms involving how genes are transcribed and old proteins are recycled, are also likely to be involved in this complex condition. 

Meanwhile, the studies also found that the common and rare variants implicated overlap significantly with genes involved in other brain disorders including autism, epilepsy and developmental disorders.

The SCHEMA study identified a spectrum of risk where more damaging mutations in the genes were associated with more adverse consequences and more severe disorders. It is hoped that these findings will have wider implications across a range of brain disorders. 

“We realised early on that only large scale collaborations would yield the kind of power needed to make real breakthroughs. It has been a privilege to work with international colleagues through PGC and SCHEMA to make this happen,” Prof Corvin added.

Scientists at TCD and NUIG, funded by Science Foundation Ireland (SFI) and the National Institute of Mental Health in the US, are building on this work to develop more detailed datasets and to explore the molecular mechanisms involved.

Both studies are published in the journal, Nature.