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April Two international landmark studies reveal clear genetic signals for schizophrenia: NUI Galway and Trinity research
Two international landmark studies reveal clear genetic signals for schizophrenia: NUI Galway and Trinity research
Representing the culmination of more than a decade of research, two breakthrough papers published in the journal Nature [today, Wednesday April 6, 2022] have identified more than 280 regions of the genome that contribute to the genetic risk of developing schizophrenia. The work has involved the efforts of researchers from more than forty countries and the participation of more than 300,000 people. Trinity College Dublin and NUI Galway researchers, led by Professor Aiden Corvin and Dr Derek Morris respectively, studying data from over 2,000 patients in Ireland contributed to both studies.
Current treatments for schizophrenia, which affects almost 1% of the adult population, are only partially effective, reflecting limited understanding of the biology involved, which has frustrated efforts to develop better treatments for many decades.
In the first of these studies the Psychiatric Genomics Consortium (PGC, of which both Trinity NUI Galway are members) reported an investigation of almost 70,000 patients and 240,000 controls. The study, an analysis of genetic variants that are common in the population, identified 287 genomic regions that have subtle, small effects on schizophrenia risk across the population. These findings were concentrated in genes expressed in the central nervous system, particularly those implicated in synaptic organization, 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”, said Professor Aiden Corvin, from the Psychiatric Research Group at Trinity College.
These findings represent a significant advance, by explaining a quarter of the genetic variance in schizophrenia susceptibility they represent a framework for further discovery. Although many if not 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%.
Dr Derek Morris, Director of the Galway Neuroscience Centre, and geneticist at NUI Galway, 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. The findings suggest abnormal neuron function in schizophrenia affects many brain areas, which could explain its diverse symptoms, which can include hallucinations, delusions and problems with thinking clearly.”
A second study, published in parallel in Nature took a different approach to provide a clearer view of the molecular mechanisms likely to be responsible. This work, coordinated by researchers at the Broad Institute of Harvard and MIT and published by the international SCHEMA Consortium (of which Trinity is a member) involved many of the same samples. The focus here was 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 1 in a 1,000 cases), and were only confirmed because of the scale of the study, which involved genome sequencing of 24, 248 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.
Dr Joshua Gordon, Director of National Institute of Mental Health, United States (NIMH), 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 for this serious mental illness.”
Both studies, when examined together show the importance of the regulation of synaptic function across the brain in the development of schizophrenia. However, both 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.
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. This offers hope that biological insights from this work will have wider implications across brain disorders.
Professor Aiden Corvin, Psychiatric Research Group at Trinity, said: “More than 3,000 Irish people have participated in our gene discovery programme over more than twenty years. 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.”
Scientists at NUI Galway and Trinity College, funded by Science Foundation Ireland (SFI) and the NIMH are building on this work to develop more detailed datasets and to explore the molecular mechanisms involved.