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National Center for Neuropsychiatric Genetics and Molecular Neuroscience

National Center for Neuropsychiatric Genetics and Molecular Neuroscience. THE UNIVERSITY OF CHICAGO HOSPITALS THE BIOLOGICAL SCIENCES DIVISION. October 2004.

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National Center for Neuropsychiatric Genetics and Molecular Neuroscience

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  1. National Center for Neuropsychiatric Genetics and Molecular Neuroscience THE UNIVERSITY OF CHICAGO HOSPITALS THE BIOLOGICAL SCIENCES DIVISION October 2004

  2. Little is known about the causes of the major mental disorders, beyond the neurobiology of pharmacologic treatment agents and the fact that they can result from inherited susceptibility to illness. • Specific genes have been associated with particular mental disorders, but biological mechanisms and molecular targets for new treatments remain largely elusive.

  3. Familial Spectrum of Bipolar Disorderincludes normal variants of human behavior, with shared genes • Schizoaffective, Bipolar type • Chronic Mania • Bipolar I • Manic episodes, usually depressive episodes • Bipolar II • Hypo manic episodes, depressive episodes • Recurrent Major Depressive Disorder • Cyclothymic Personality • Includes people with sense of luck, energy, optimism, creativity, no psychiatric disturbance

  4. The Underlying Causes of Mood Disorders and Schizophrenia • Genes • Environment At this time, it appears most feasible to discover the genes first and then identify their environmental interactions.

  5. Path to Genetic Discoveries genes for mental illnesses cloned at U of Chicago and elsewhere; function still being studied 2003 first human whole genome map based on DNA markers 1987 gene for Huntington’s Disease fully cloned, function still being studied 1993 human gene map becomes feasible 1978 chromosomal mapping of genes 1911 Human Genome sequence 2001 1989 NIMH begins its genetics initiative; large number of families contribute DNA and diagnostic information 1952 Watson and Crick discover how DNA codes genetic information 2002 meta-analysis at U of Chicago locates susceptibility gene regions for SZ and BP 1983 chromosomal map location of Huntington’s Disease based on DNA markers 1995 Statistical methodology for common, complex inheritance disease. U of Chicago is a leader.

  6. A Timely Opportunity Predict Susceptibility, Develop New Treatments, Predict Treatment Response and Adverse Events Human Genome Project Understand mechanisms of illness Illness gene discovery through Reverse Genetics/ Forward Genetics

  7. Recently Discovered Susceptibility Genes

  8. Discovery of Susceptibility Genes in Complex Inheritance Disorders • Problems • Weak effect genes acting together • Correct genetic model lacking • Difficulties of replication • Complex and variable set of behaviors associated with same genes • Solutions • Non-parametric statistical inheritance models • Study of very large samples and very large numbers of genetic markers • New scientific strategies for gene interrogation • Bioinformatics • Informed by neurobiology and genomics

  9. Long-term Goals of Susceptibility Gene Research • Identify all genes conferring risk, and: • Biological role of each gene • Variability in human behavior produced by each component gene • Environmental and epistatic interactions of each gene • Predict treatment response and adverse effects of current treatments • Develop targeted treatments and individualized applications of drug therapies • New and safer or more effective treatments • Better outcomes for individual patients and relatives • Interventions for persons at high risk James D. Watson 1947 BSc University of Chicago 1962 Nobel prize for discovery of structure of DNA and its role in genetic information transfer 1968 Director of Cold Spring Harbor Laboratories; revived into a National Center for Human Genome Research

  10. An Aggressive Plan: A National Center at the University of Chicago • Expand clinical focus from Bipolar Disorder to include Schizophrenia and Recurrent Major Depressive Disorder • Develop transgenic mouse models of susceptibility genes identified in human studies, such as BDNF, the G72/G30 gene complex • Develop new bioinformatics software • Develop and employ new statistical methods for genetics of complex disease • Acquire new technologies rapidly – Comparative Genomic Hybridiziation • Investigate genetics of specific features of mental disorders and related personality variants

  11. What is a Center? • Several national leaders with interconnecting projects and disciplines • An atmosphere of support and encouragement • A critical mass of investigators and students • A source of seed funding for pilot projects and new ideas • More than the sum of its parts

  12. Why the University of Chicago? • Prominent university with a critical mass in human genetics, statistics, neurobiology, and specific mental disorders • Intellectual environment where diverse disciplines foster integrative research, creativity and progress • Dedication to cutting-edge research and track record of achieving breakthroughs

  13. University of Chicago Discoveries of Genes for Complex Inheritance Disorders • Calpain10 association with diabetes mellitus (2002) • G72/G30 is associated with Bipolar Disorder (2003) • NOD2 association with inflammatory bowel disease (2003) This is a significant proportion of all the successful positional cloning of susceptibility genes for complex disorders to date.

  14. The University of Chicago Offers National Leadership • Elliot S. Gershon, Professor of Psychiatry and Human Genetics Discovery of chromosome 13 linkage region for Bipolar Disorder, and that the G72/G30 gene complex in that region is responsible for susceptibility. • Nancy J. Cox, Professor of Human Genetics Statistical analytic models for combined linkage and association analysis. This led to first success of positional cloning in a complex inheritance disease (non-insulin-dependent diabetes mellitus). • T. Conrad Gilliam, Chair and Professor of Human Genetics Genetic determinants of common heritable disorders including schizophrenia, autism, anxiety disorder, bipolar disorder, and cardiovascular disease using novel genomic and bioinformatics approaches. • Edwin H. Cook, Professor of Human Genetics, Psychiatry, and Pediatrics Molecular genetics of pediatric onset neuropsychiatric disorders, using neurochemical and molecular genetic research tools. • Sangram S. Sisodia, Professor of Neurosciences Cell biological, mouse transgenesis and neurobiological approaches to help define and test new targets for therapeutic intervention of Alzheimer’s Disease.

  15. Philanthropic Need

  16. Strategies for Discovery of Susceptibility Genes When Inheritance is Complex • Positional Cloning (reverse genetics) • A chromosomal region containing a susceptibility gene is located, then the genes within the region are tested to determine which gene contributes to susceptibility. • Candidate Genes (forward genetics) • Genes are tested based on biological hypothesis of illness or of treatment. • Differential Gene Expression • Expression of many genes is compared in brain tissues of patients vs. controls. • Whole-genome Association • Every gene in the genome is tested for association with illness. These strategies follow from research that indicates that susceptibility to Bipolar disorder, Schizophrenia, and Major Depression stems from multiple genes with complex interactions among them. ADDENDUM

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