Psychosis Research Group
[Neuropsychiatric Genetics Laboratory]
Schizophrenia and bipolar disorder, the major psychotic disorders, affect more than one in every hundred Irish adults. They are known to be substantially heritable but remain poorly understood. The goal of the Psychosis Research Group is to identify and investigate risk genes for psychosis as a means of improving understanding of disease biology, to develop better methods of diagnosis, and to establish new therapeutic approaches. We have been working with affected Irish people, their families and healthy volunteers since 1996 and more than 3,000 people have participated in our studies to date (see Recruitment). Recent successes in the discovery and investigation of risk genes are beginning to translate into new insights into the molecular basis of these devastating disorders (see our Key Developments).
We are a multidisciplinary team of clinicians, neuroscientists, psychologists, geneticists, biostatisticians and biologists. The group is lead by Prof. Aiden Corvin with Principal Investigators Prof. Michael Gill, Prof. Gary Donohoe, Prof. Derek Morris and Dr Daniela Tropea. We are based at the Department of Psychiatry and Institute for Molecular Medicine, Trinity Centre for Health Sciences, St Jamesís Hospital, Dublin. To expand our investigation of how risk genes function, Dr Tropea will shortly be opening a new functional biology laboratory at the TCD Biomedical Sciences Institute.
Our Current Staff
Prof Aiden Corvin (Group Leader)
Prof Michael Gill (PI)
Prof Gary Donohoe (PI)
Prof Derek Morris (PI)
Dr Daniela Tropea (PI)
Dr Kristin Nicodemus (PI)
Dr Paul Cormican (Postdoctoral researcher in Bioinformatics)
Dr Elaine Kenny (Postdoctoral Researcher in Genetics/Bioinformatics)
Dr Emma Rose (Postdoctoral researcher in Neuroimaging)
Dr Heike Schmidte (Postdoctoral researcher)
Dr Carlos Pinto (Database Manager)
Dr Eric Kelleher (Clinical Research Fellow)
Denise Hogan (Clinical Research Nurse)
Christina Mooney (Clinical Research Nurse)
Catherine Delaney (Clinical Research Nurse)
Dr Ines Molinos (Research Assistant)
Stefania Bellini (PhD student)
Ciara Fahey (PhD student)
Sarah Furlong (PhD student)
April Hargreaves (PhD student)
Sinead Kelly (PhD student)
Alison Merikangas (PhD student)
Omar Mothersill (PhD student)
Deirdre Robertson (PhD student)
Dr Liz Cummings (MD student)
Carol O’Brien (Research Assistant)
As a consequence of the Human Genome Project, in the last five years we have been able to investigate genetic variation (DNA) in the genome on a scale that was previously unimaginable:
- The group has played a significant role in large collaborative genome-wide association studies (GWAS) in both schizophrenia and bipolar disorder, published in Nature Genetics in 2011, identifying 11 chromosomal regions which increase risk to schizophrenia, bipolar disorder, or both: (http://www.tcd.ie/Communications/news/pressreleases/pressRelease.php?headerID=2054&pressReleaseArchive=2012).
- Individually these regions are likely to play a small part in overall illness risk, which is likely to involve many small effects (polygenes) interacting with each other and with environmental risk factors. In 2009, we identified that this ‘polygenic component’ is likely to contribute to risk of both schizophrenia and bipolar disorder, indicating that they have a partially shared aetiology: (http://www.ncbi.nlm.nih.gov/pubmed/19571811).
- We have developed methods to examine whether these small effects involve specific molecular pathways, in the process implicating neuronal cell adhesion and membrane scaffolding mechanisms in psychosis (http://www.ncbi.nlm.nih.gov/pubmed/20157312)
- Like with a jigsaw puzzle, having a more complete picture of the risk genes will tell us more about the molecular pathways and biology involved in psychosis. With this aim, Prof Corvin is the lead PI for Schizophrenia with a large international effort to identify risk genes for 15 common disorders or traits as part of the Wellcome Trust Case Control 2 (http://www.wtccc.org.uk/ccc2/) and the group continue to contribute to the worldwide discovery effort through the Psychiatric Genomics Consortium (https://pgc.unc.edu/).
- What impact do these small genetic effects have on people? We have published a series of studies investigating how these effects impact on cognitive performance, clinical symptoms and even brain structure (http://www.tcd.ie/Communications/news/pressreleases/pressRelease.php?headerID=1506&pressReleaseArchive=2010).
- These studies are also proving very informative in helping us to understand how the brain processes information and performs different cognitive functions (http://www.ncbi.nlm.nih.gov/pubmed/21520349).
- As part of the International Schizophrenia Consortium, we identified that for a small subset of patient’s larger deletions or duplications of parts of chromosomes may be contributing more substantially to disease risk (http://www.tcd.ie/Communications/news/pressreleases/pressRelease.php?headerID=964&pressReleaseArchive=2008).
- In 2011, with US colleagues we identified that for some of these patients, having duplications of the gene VIPR2 may be important in increasing disease risk (http://www.tcd.ie/Communications/news/pressreleases/pressRelease.php?headerID=1707&pressReleaseArchive=2011). Currently work is underway to identify whether expression of this receptor can be regulated in these patients using novel therapies including synthetic neuropeptides.
- Making these incremental discoveries has required us to innovate and to develop new methods of investigating genetic data (http://www.ncbi.nlm.nih.gov/pubmed/21589856; http://www.ncbi.nlm.nih.gov/pubmed/21163834; http://www.ncbi.nlm.nih.gov/pubmed/19620097).
As technology improves and we learn more about psychosis our focus is changing. We are:
- Identifying rare risk variants, using next-generation sequencing methods (e.g. at our TCD genome sequencing facility http://www.medicine.tcd.ie/neuropsychiatric-genetics/functional-genetics-genomics/sequencing.php).
- Planning to explore how such variants affect families.
- Performing functional studies of risk genes (e.g. using cellular models) to understand how genetic variation impacts on gene function (http://www.ncbi.nlm.nih.gov/pubmed/20636642).
- Developing a Translational Research programme to study the function of risk genes in vivo and in vitro, to explore how these genes impact on neurobiology and to see whether the changes that they induce can be reversed by treatment (http://medicine.tcd.ie/neuropsychiatric-genetics/functional-genetics-genomics/translational-research.php).
We are grateful to all our current and past participants, without whom none of this work would be possible. We are still recruiting and working with patients and their families. The assessment involves a clinical interview and a simple blood sample. If you would like more information please let us know at (01) 8962465 or by contacting Dr Eric Kelleher at Eric.Kelleher@tcd.ie.
- Irish Times article (2008)
- Irish Independent (2008).
- Belfast Telegraph (2008)
- RTE- Mind Matters-on Schizophrenia (2007)
Outputs Work by the group has been published in 84 peer-reviewed articles (to October 2011) in leading journals including Nature, Nature Genetics, Archives of General Psychiatry, Molecular Psychiatry, Biological Psychiatry and the British Journal of Psychiatry. Our work has been presented internationally at meetings including the World Congress on Psychiatric Genetics, the American Society for Human Genetics, the Society for Neuroscience, the European Society for Human Genetics, Keystone Meetings and the Schizophrenia International Research Society. Nationally we disseminate our findings to our participants, national advocacy networks, clinicians and the HSE.
Four students have completed their PhD projects on this programme to date.