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Biomarkers for Suicidal Behavior, Stem Cells, and Epigenetics of Cocaine Addiction Highlight Second Day of World Congress of Psychiatric Genetics in Boston

On the second day (Friday, October 18) of the XXIst World Congress of Psychiatric Genetics meeting in Boston, Alexander Niculesca, M.D., Ph.D., Associate Professor in the Department of Psychiatry at the Indiana University School of Medicine, described his group’s ground-breaking work in identifying and validating blood biomarkers for suicidal behavior, in particular the identification of a panel of six markers whose levels in the blood can help predict the risk of future hospitalizations for suicide. Dr. Niculesca emphasized the significance of these findings by noting that one million people die each year from suicide and that someone commits suicide every 40 seconds. Furthermore, the omega-3 fatty acid DHA (docosahexaenoic acid), which is a major component of the human brain, cerebral cortex, skin, sperm, testicles, and retina, can be used in the diet to reduce the suicide risk in some at-risk patients. Consequently, the ability to identify patients at high risk of suicide through simple blood tests has the potential to save lives. The most powerful predictor of the six markers in the panel was the protein coded for by the gene SAT1. SAT1 codes for the rate-limiting enzyme in the catabolic pathway of polyamine metabolism. Dr. Niculesca’s work is an example of the use of a comprehensive convergent functional genomics approach to identify risk-related genes. The results of this work were published online on August 20, 2013 in an open-access article in Molecular Psychiatry. Following Dr. Niculescu’s talk, Rakesh Karmacharya, M.D., Ph.D., Assistant Professor of Psychiatry at Harvard Medical School, described the use of induced pluripotent stem (iPS) cells that were differentiated to neuronal cells in order to look for cellular signatures of schizophrenia and bi-polar disorder in patient-derived cells. Proof of principle for this approach was established in a study of Rett syndrome in a 2010 article in Cell. In Dr. Karmacharya’s work, this approach, gets around the problem of not being able to test tissue samples of brains from living patients and represents a possibly immensely powerful approach to the study of disease. Dr. Karmacharya used his system to screen the pathway perturbation effects of 320 small molecules. In one of the afternoon sessions, there were a number of presentations related to epigenetics and cocaine addiction. In the first, Jian Feng, Ph.D., a post-doctoral fellow in neuroscience in Dr. Eric Nessler’s lab at Mount Sinai Hospital in New York, used ChIP-seq and RNA-seq in a mouse study to identify a potentially important, epigenetically modified gene of possible functional biological significance in cocaine addiction. The gene is Rbfox1 (also called A2BP-1). In a later talk, R. Christopher Pierce, Ph.D., Professor of Neuroscience in Psychiatry at the Perelman School of Medicine, University of Pennsylvania, presented evidence suggestive of the inheritance of epigenetic changes in the father that were transmitted to the male, but not the female, offspring of a mouse father that had developed a cocaine resistance phenotype. Dr. Pierce concluded that cocaine can reprogram the sperm epigenome. The day had started with a plenary session featuring a stimulating panel discussion entitled “Defining Mental Illness through Genetics,” or, as alternatively titled by panel chair Steve Hyman, M.D., “DSM Meets Psychiatric Genetics.” The DSM is the Diagnostic and Statistical Manual of Mental Disorders, which seeks to provide a common language and standard criteria for the classification of mental disorders. The DSM is currently in its fifth edition (DSM-V). Dr. Hyman is currently Director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. He was previously Provost of Harvard University and Director of the National Institute of Mental Health (NIMH). Other members of the distinguished panel included Professor Jan Buitelaar, Chairman of the Department of Psychiatry and Child Psychiatry at the Donders Institute Center for Neuroscience, Raboud University in the Netherlands; Bruce N. Cuthbert, Ph.D., Head of the NIMH’s Division of Adult Translational Research and Treatment Development; Kenneth Kendler, M.D., Professor of Psychiatry, Professor of Genetics, and Director of the Psychiatric Genetics Research at the Medical School of Virginia Commonwealth University; Michael Owen, Ph.D., Director of the Medical Research Council’s Centre for Neuropsychiatric Genetics and Genomics, and Deputy Head, Cardiff University School of Medicine; and Myrna Weissman, Ph.D., Professor of Epidemiology in Psychiatry at Columbia University in New York. In the introduction to the discussion, it was noted that the validity of the DSM has been widely challenged and that the NIMH has recently launched an effort, called the Research Domain Criteria (RDoC) to reconceptualize mental illness “from the bottom up,” drawing on neuroscience and genetics to provide alternatives to purely descriptive nosology (the classification of diseases). The panel sought to address the issue of what genetic research can tell us about the structure and boundaries of psychiatric disorders. Dr. Hyman led off with a statement that DSM-III was “an attempt to define homogeneous groups using a breathtaking degree of unwarranted splitting,” that resulted in classifications that were both “too narrow” and “too broad,” with “thresholds that are too broad.” He emphasized that there is now much evidence for continuous gradients cutting across multiple disorders that do not mesh with the discontinuous categories of the DSM and that would be better addressed by the use of “dimensions.” Finally, he said that, in his opinion, “it is not clear how much genetics will be useful in diagnostics.” In fact, “it won’t,” he opined. Dr. Kendler followed and began by describing himself as a “DSM warrior.” He outlined six phases of past and future progress in psychiatric disease nosology. Phase 1 was German psychiatrist Dr. Emil Kraepelin, who died in 1926, but was described by Dr. Kendler as a brilliant diagnostician who is credited with developing the first differential diagnosis between major depression and schizophrenia. Phase 2 is represented by a short 1970 paper by Dr. Eli Robins and Dr. Samuel Guze demonstrating that five phases of research are needed to demonstrate that a diagnostic concept represents a disease. Phase 3 is twin studies that showed the meta structure of many disorders. Phases 4-6 are the period of molecular genetics. Phase 4 is the candidate gene phase, which was not very useful, according to Dr. Kendler who described SNPs as “nosologic castles in the sand.” Phase 5 is represented by genome-wide association studies (GWAS), which Dr. Kendler said allowed the asking and answering of far more interesting questions. Finally, Phase 6 is that of polygenic scores, which essentially recreate aggregate scores of twin studies and have the potential to provide molecular validation of psychiatric disease studies. Dr. Kendler concluded by stating that genetics has an important and increasing role in psychiatric disease studies. Dr. Weissman emphasized the role of environment, both in utero influences and the influences of various forms of social deprivation, and the related role of epigenetics in these environmental effects. Dr. Buiteleer emphasized the needs to investigate gene interactions and to identify new targets for medicines, and he highlighted the convergence of genetics and imaging. He stressed the needs to focus on functionality and to integrate studies with metabolic issues, immunology, and energy metabolism. Dr. Owen noted the need to understand the underlying biology of the psychiatric diseases and remarked on the extensive pleiotropy that is already being seen in these diseases. Finally, Dr. Cuthbert described the NIMH’s new RDoC effort and indicated that it will potentially provide a precision medicine approach. The panel then fielded questions from the audience, which was clearly stimulated by the wide-ranging and highly pertinent discussion. The World Congress of Psychiatric Genetics will run through Monday, October 21, 2013. [Molecular Psychiatry article] [Nature news article on suicide biomarkers] [Science news article on suicide biomarkers] [Press release on suicide biomarkers] [BioQuick article by Michael D. O'Neill]