Since 1987 when the Clinical Brain Disorders Branch (CBDB) was created, its resources have been focused on understanding neurobiologic mechanisms of neuropsychiatric disorders, particularly schizophrenia. The mission of the Branch is to make major scientific discoveries that will lead to a meaningful understanding of schizophrenia and related disorders and that will lessen the suffering of affected patients and their families. With the capability to identify genetic risk factors for schizophrenia, the first objective clues to the etiology of these disorders have emerged. This has led to a transformation of research in CBDB beginning in 1996, from earlier studies aimed at characterizing the neural systems and molecular phenomenology associated with schizophrenia using cognitive and imaging approaches and postmortem tissue assays, to focus on underlying genetic mechanisms. The primary objective of our ongoing work is to translate genetic variation related to schizophrenia into the biologic and clinical mechanisms of the disorder and ultimately into prevention and more effective treatment. Genetic association with clinical diagnosis is not undertaken as a primary goal per se but rather as a compelling starting point to generate and test hypotheses about biological mechanisms of illness and to discover new therapeutic targets. .

Candidate genes for generating hypotheses about molecular mechanisms are identified from genetic association in our own clinical datasets, from other studies of association, and from known interacting biological pathways and networks. A fundamental guiding principle of our studies is that the genes related to risk for schizophrenia are not fundamentally responsible for the diagnostic symptoms, but instead control biological processes related to relevant brain developmental programs and functions. Just as recent structural copy number variations (CNVs) associated with schizophrenia have been shown to be relevant to a broad phenotypic spectrum related most robustly to cognitive deficiency, we expect that common alleles in genes associated weakly and inconsistently with risk for the diagnosis of schizophrenia will show greater penetrance and effect size on biological phenotypes associated with risk for schizophrenia, including molecular effects in tissue and physiological characteristics in brain. A similar approach has been employed in the investigation of other complex genetic disorders, such as adult onset diabetes, in which multiple genes each account for only a very small share of the risk but show stronger effects on related intermediate phenotypes even in normal subjects— e.g. body mass index or glucose induced insulin release. Association of schizophrenia risk-associated alleles with relevant biological phenotypes is a principal goal of our strategy for validation and characterization of genetic mechanisms of susceptibility.

In our clinical studies, polymorphisms in over twenty five genes have been associated with schizophrenia. In addition, we have identified rare CNVs in several individual cases that may be associated with schizophrenic symptoms. While there is active debate about the trade-offs in strategies for confirmation of genetic association in complex disorders such as schizophrenia, about the conclusiveness of statistic evidence for any particular gene, and about the complexity of gene-gene and gene-environment interactions in the risk architecture of illness, we have concentrated on validation and characterization of genetic mechanisms by hypothesis testing of convergent biological effects of genetic variation in candidate gene networks and pathways. We have pursued this approach at the level of gene processing in postmortem human brain, in relevant cell model systems, in animal models and ultimately in studies of living human brain. Our evolving emphasis is to explore epistatic interactions of multiple genes at all these various levels of analysis, as this approach is more likely to reflect the complex genetic architecture of this condition, to define pathogenic molecular pathways, and to identify potential therapeutic targets in these pathways.

Historically, researchers in CBDB have had a substantial impact on the landscape of schizophrenia research and on the lives of schizophrenic patients. Specifically: 1) CBDB is largely responsible for generating the hypothesis that the origins of schizophrenia involve factors affecting brain development; 2) CBDB has played a principal role in the worldwide research renaissance of the analysis of postmortem human brain tissue; 3) CBDB is largely responsible for the demonstration that cognitive dysfunction is a core manifestation of schizophrenia and of genetic risk for schizophrenia, and for cognition in schizophrenia being a centerpiece of academic and industry research worldwide; 4) CBDB is responsible for the initial reports of the majority of the replicable body of major neuroimaging findings that have been associated with schizophrenia and with genetic risk for schizophrenia; 5) CBDB is responsible for the development of the first high fidelity animal model of schizophrenia that reproduces a diverse constellation of pharmacological, molecular, developmental and behavioral phenomena associated with the illness, which is widely used in research groups around the world; 6) CBDB is responsible for the first demonstration in human subjects of specific genetic effects of common alleles on brain mechanisms related to human cognition, emotion, and temperament. This progress is exemplified by our findings that three genes weakly related to psychiatric disorders (i.e. COMT, BDNF, and 5�HTTLPR) are strongly related to cognitive and emotional processing in brain, discoveries cited in the 2003 annual "breakthrough of the year" edition of Science as centerpieces of the second biggest scientific breakthrough of 2003 ("decoding mental illness"). CBDB has also introduced a new and exploding area of scientific inquiry based on brain mapping related to genetic variation, called, "imaging genetics;" and CBDB pioneered a paradigm shift in psychiatric genetics, moving the field from mapping illness loci to identifying gene effects on information processing and molecular pathology in human brain.

A primary goal of ongoing research is to use evidence of genetic association to generate and test hypotheses about how specific genes affect brain development/plasticity and function and how these effects relate to the biology and potential treatment of the illness. This goal mandates a multidisciplinary team approach and this approach necessitates a unique research environment. To create this unique structure, CBDB became part of a multi-Institute program called, Genes, Cognition and Psychosis (GCAP), which was created in 2004. GCAP supports the work of investigators in NIMH, NCI, NINDS, and NICHD and collaborative groups outside of NIH, including investigators at Oxford University - UK, University of Bari - Italy, Armenian National Academy of Sciences - Armenia, and the Utah School of Medicine - USA. In addition to having directly supported the work of ten NIH PIs, GCAP provides resources for seven Core projects that are used by all PIs in GCAP and also by collaborative groups outside of GCAP. These Cores are a Clinical Core headed by Jose Apud, M.D., Ph.D. which provides clinical support for and supervision of the outpatient family studies and the in-patient experimental therapeutics unit; a Mouse Transgenic Core headed by Jingshan Chen, M.D., Ph.D.; a Neuroimaging Core facility headed by Venkata Mattay, M.D.; a Genetics/Bioinformatics Core headed by Richard Straub, Ph.D.; a Postmortem Tissue Core headed by Thomas Hyde, M.D., Ph.D.; and a Cell Culture Core head by Yoshi Sei, M.D., Ph.D.