Recently, specific genes have been identified as associated with particular mental illnesses. However, research has not yet undiscovered the biological mechanisms by which these susceptibility genes act and, consequently, new treatments remain to be developed. Because various genes may play a role in drug response and toxicity, the targeting of genes is a complex process. Identification of susceptibility genes coupled with genetic testing to identify genes affecting drug response in individual patients will lead to novel approaches in individualized application of drug therapy.

New technology and data available through the Human Genome Project offer an opportunity to evaluate and study mental illnesses as never before. Additionally, successes in reverse genetics now enable scientists to uncover biological mechanisms of illness and potential treatment response from information on genetic markers in individuals and families with illness. Reverse genetics is a process that enables scientists to discover a gene associated with an illness or behavior. First, they find its rough location from genetic markers, followed by identifying the actual gene through further statistical research on patient samples. While the function of the gene is frequently unknown, when the gene's normal function is discovered (which is generally feasible), the biological effects of the causative variant often remains to be discovered through further research.

This unexpected outcome of disease gene associations has occurred in many instances of inherited common disease, including several recently discovered genes associated with major mental disorders. One method to discover the functional role of the disease-associated gene is to introduce genetic variants into a cloned DNA segment, which enables scientists to examine how this mutation affects the function of the gene's expressed protein. This approach, which can be applied in various cellular and tissue models, as well as in transgenic mice, is increasingly important as new genes are identified and targeted therapies proposed.

Traditionally the discovery of susceptibility genes for Bipolar Disorder and Schizophrenia was thought to be among the most intractable problems in human genetics. However, in the past few years, a number of replicated gene associations have been reported for these and other common diseases with complex inheritance. Recent discoveries of genes for complex inheritance disorders attributed to University of Chicago scientists include:

• Discovery of the G72/G30 association with bipolar disorder
• Discovery of the NOD2 association with inflammatory bowel disease
• Discovery of the Calpain10 association with diabetes mellitus

The University of Chicago is committed to leveraging its expertise and national leadership to drive progress in cutting-edge research and generate important new advances in neuropsychiatric disorders and related basic sciences. Such research represents the best long-term hope we have to overcome severe mental illness. Scientific breakthroughs will lead directly to improved treatments by targeting newly discovered genes and the proteins they produce. They also will target interventions to the particular patient, by predicting therapeutic response and susceptibility to adverse effects of each drug treatment, based on the patient's genotypes.

In partnership with the philanthropic community, the University is launching a focused research center to study safer and more effective individualized treatments. Under the leadership of renowned psychiatrist and genetics researcher Dr. Elliot S. Gershon, the Center for Neuropsychiatric Genetics and Molecular Neuroscience presents an opportunity for strategic growth and formalized collaboration among a multidisciplinary team of physician researchers and other scientists. This team of leading investigators includes experts in genetics, transgenics, bioinformatics, neurobiology, and statistics. It will examine function of genes in the mammalian brain in various models, including behavior, cell biology, and transgenic mice. With the shared objective of developing new treatments for psychiatric disorders, the convergence of these disciplines will stimulate progress and new insight into psychiatric disorders and other malfunctions of the brain. The Center, with its innovative science and expected translational benefits into clinical diagnosis and treatment, will also accelerate discovery in neurobiological research.

The Center is expected to be self-sustaining through federal grants, marketing of gene discoveries to biotechnology and pharmaceutical corporations, and continued philanthropic interest by individual donors. With an initial goal of securing $5 million in philanthropy, the first phase of the Center will focus on expanding research efforts in bipolar disorder to include translational genetic research on other major mental illnesses, and on statistical genetics.

• Genetic research on Bipolar Disorder will expand to include Schizophrenia and Recurrent Major Depressive Disorder, aggressively advancing work to develop transgenic mouse models of BDNF, the G72/G30 gene complex, and other genes of importance in psychiatric disorders. There will also be a focus on new bioinformatics software development.
• Funding of two endowed professorships, for senior faculty engaged in statistical genetics of complex disease, and clinical investigation of mental disorders. The highest commitment an institution can make to a research area is the offering of endowed professorships. These professorships will enable recruitment and retention of talent in the disciplines supported by the Center.

A MULTIDISCIPLINARY TEAM

Nancy J. Cox, Professor of Human Genetics
Dr. Cox is a pioneer in statistical analytic models for linkage and association analysis. This led to first success of positional cloning of a susceptibility gene in a complex inheritance disease (non-insulin-dependent diabetes mellitus). Cox's research is focused on the identification and characterization of genetic variation influencing susceptibility to complex disorders. Currently, this research includes an emphasis on developing robust methods for taking gene-gene interaction into account in the context of linkage mapping, linkage disequilibrium mapping, and positional cloning. A multidisciplinary collaboration with the molecular biologists and population geneticists allows a great deal of flexibility in designing and conducting research projects ranging from purely theoretical, to largely analytical, to a mix of analytic and molecular science.

Conrad Gilliam, Professor and Chairman of Human Genetics
Dr. Gilliam's internationally recognized research program studies the genetic determinants of common heritable disorders including schizophrenia, autism, anxiety disorder, bipolar disorder, and cardiovascular disease. Gilliam's group uses mouse models of behavior and cognition together with novel genomic and bioinformatics approaches to predict heritable changes in DNA that alter an individual's susceptibility to neuropsychiatric disorders.