02:30am Wednesday 23 August 2017

Study identifies biological mechanisms for schizophrenia, bipolar disorder and depression

By Louise Pratt, King’s College London

The study, led by Dr. Gerome Breen at King’s College London and Prof. Peter Holmans at Cardiff University, in collaboration with researchers at UCLA and the Broad Institute of Harvard and MIT, was conducted by the Pathways Subgroup of the Psychiatric Genomics Consortium, which involves hundreds of investigators from dozens of institutions across the globe. It is published online today in Nature Neuroscience.

Thousands of genetic differences across the human genome act together to increase the risk for psychiatric conditions such as schizophrenia. However, until now, it has not been clear how these genetic changes affect different biological processes that then go on to alter brain function.

Dr. Gerome Breen, MRC Centre for Social Genetic and Developmental Psychiatry at King’s, Professor Peter Holmans, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, and colleagues, analyzed genetic data from over 60,000 participants, including individuals with schizophrenia, bipolar disorder, major depression, autism spectrum disorders and attention deficit hyperactivity disorder, as well as healthy individuals. Their aim was to identify the biological and biochemical pathways involved in causing risk for these disorders.

Dr. Breen said: ‘When we grouped the genetic data together, we found that genes relating to histone methylation – molecular changes that alter DNA expression – and immune function are risk factors associated with the development of these disorders. Biological pathways are important as they are much broader drug targets than single genes or proteins.’

Professor Peter Holmans from Cardiff University noted ‘The use of genome-wide genetic data allows us to identify disease-relevant pathways without making prior biological assumptions. This is important as it allow us to discover novel mechanisms of risk that might not otherwise be studied.’

Dr Colm O`Dushlaine (formerly Stanley Center, Broad Institute and joint first author) continues: ‘The histone pathways we found have previously been studied in cancer and the immune pathway in infectious disease. We now have evidence of their involvement in the etiology of complex psychiatric phenotypes, a critical step towards understanding how best to develop novel therapeutic approaches.’

Professor Dan Geschwind from UCLA commented: ‘The success of this approach supports the utility of pathway and network analyses in understanding psychiatric disease, an approach which will grow more powerful as more loci are identified.’

Dr. Phil Hyoun Lee (Massachusetts General Hospital and Broad Institute and joint first author) said ‘There is plenty of evidence, including from this paper, that these processes are important in the brain. We now wish to find the exact brain regions where these processes are active.’

Dr. Breen concludes ‘This is a particularly exciting development in the study of psychiatric disease as it is a first step in identifying shared biological mechanisms that act across disorders. This will help in developing treatments that target these mechanisms, and are thus effective for a range of psychiatric illness, irrespective of exact diagnosis.’

The study is the result of many years of work by hundreds of investigators worldwide in the Psychiatric Genomics Consortium, an international, multi-institutional collaboration founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease. The PGC is currently genotyping new samples to further study these and additional psychiatric diseases, including anorexia and PTSD.

Core funding for the Psychiatric Genomics Consortium comes from the U.S. National Institute of Mental Health (NIMH), along with numerous grants from governmental and charitable organizations, as well as philanthropic donations. Work conducted at King’s College London was funded by the National Institute for Health Research Biomedical Research Centre and Dementia Unit at King’s and South London & Maudsley NHS Foundation Trust and Cardiff University by the MRC and the Wellcome Trust. Work at the Broad Institute’s Stanley Center for Psychiatric Research was funded by Sylvan Herman Foundation and the Stanley Medical Research Institute.

Paper cited: Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nature. Online January 19, 2015. Doi: 10.1038/nn.3922 


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