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Genomics of Human Disease

Leaders: Prof. Michael Gill, Prof. Ross McManus, Prof. Louise Gallagher and Prof. Aiden Corvin.

We work to understand the genetic causes of disease, with a particular focus on common diseases. As technology has progressed so have we; our focus has shifted from investigating individual candidate genes to whole genomes. This is important, as by investigating the whole genome, it gives us a much greater opportunity to identify novel risk genes and molecular mechanisms which can improve our understanding of disease biology. This is the first translational step towards developing new diagnostic approaches and therapies. With access to large patient cohorts and the HRB/Wellcome Trust CRF, we are strategically positioned to identify which patients will benefit most from new molecular diagnostic tests or targeted pharmacogenomics approaches and to deliver improvements in care to our patients.

We have made significant breakthroughs in understanding a wide range of different disorders in our key research areas of Neuropsychiatric Genetics, Genomic Research, Translational Immunology and Cancer. Work from the institute has been published in Nature, The New England Journal of Medicine, Nature Genetics and Nature Immunology.

Neurosciences

In the Neurosciences, researchers at the Neuropsychiatric Genetics Laboratory have been involved in key breakthroughs in our understanding of disorders including schizophrenia, bipolar disorder and autism. Our work has confirmed that schizophrenia and bipolar disorder are genetically related disorders and we have identified a number of risk genes implicating cell signalling, cell adhesion and immune pathway mechanisms. We have been involved in discovering new risk genes for autism and identifying molecular risk pathways for the disorder. We also work on cellular and animal models to understand the mechanisms involved.

Genomic Research

The focus of this group is investigating common diseases caused by inflammation (e.g. coeliac disease, psoriasis and psoriatic arthritis and inflammatory bowel disease (IBD)) and system responses to inflammation and infection. We have been centrally involved in the international consortia involved in investigating the genomic causes of coeliac disease we and we have contributed to the identification of over 40 new risk genes for the disorder, principally in pathways regulating control of the immune response. This work has been funded by the Wellcome Trust, SFI and the HRB, and we are currently funded by the SFI to investigate expression of susceptibility genes at the cellular level using next generation approaches including the immunochip platform. We have also shown an overlap in susceptibility genes for type 1 diabetes and coeliac disease. Recently we have been involved in mapping susceptibility genes for psoriasis and psoriatic arthritis, and are currently involved in a study to predisposing factors for esophageal disease, which contributes to cancer susceptibility. We have also demonstrated an association between IBD and genes of the xenobiotic response system. We are interested in understanding the host factors important in the response to infection and in particular, what determines the development of sepsis, a devastating illness with high mortality rates which has shown little improvement in outcome for many decades. We have shown that people who develop post-operative infection and sepsis have deficient pro-inflammatory cytokine expression, (e.g. IL-2 and IL-7) in peripheral blood leukocytes, leading to an inadequate immune response, which may predispose to the onset of infection. Based on our research, we have identified a set of genes whose expression can be integrated to give a highly predictive algorithm allowing the identification of patients at risk, or not, of this disease, and also indicated potentially improved therapeutic approaches.

Translational Immunology

This group works to understand how and why immune function is impaired in diseases like asthma and eczema. Our research involves the translational spectrum from genetics discovery (e.g. identifying the filaggrin risk gene for eczema) to identifying a novel mouse model for eczema based on this discovery.

Cancer

The Genomic Research Group has worked closely with the Department of Surgery in the investigation of genomic factors predisposing to Barrett’s Esophageous, a recognised predisposing factor for Esopheageal Cancer. This work has led to significant findings relating to the involvement of IL-18 in this process and other findings from the International Barrett’s Esophageous research consortium currently in press at Nature Genetics.