As the discovery of the genetic substrates of neuropsychiatric disorders is hoped to lead to improved pathophysiologic understanding, enhanced treatments and relief from stigma for both the affected individuals and the field, the lack of strong, reliable and translatable genetic findings is a critical problem. My long-term goal is to contribute to the development of analytic methods that will ultimately enable the identification and characterization of genes contributing to risk for neuropsychiatric disorders. Ultimately, such information will contribute to advances in the phenotyping and treatment of major psychiatric disorders. To accomplish this end, I believe the most fruitful strategies will involve statistical and computational approaches to hypothesis-testing using the presently abundant genetic, genomic and bioinformatics data relevant to the etiology and pathophysiology of psychiatric disorders. The research planned under my K08 award seeks to address one of the greatest challenges facing psychiatry today, which is not how it will collect new and better data, but how it will translate the massive repositories of genetic, biological and bioinformatics data into better understanding of disease and rational clinical care.
The objective of my current NIMH K08 Mentored Career-Development Award is to develop my career and research trajectories through continuing multidisciplinary training and mentorship in the fields of molecular biology, statistical genetics, bioinformatics and computational biology. The specific goals of my K08 research project are: 1) to use pathways-based and functional genomic analyses to identify gene sets, defined in terms of shared biological attributes-including ontologies, biological pathways, protein domain structure, orthology and brain expression signatures-that are most likely to contain general and disease-specific susceptibility genes across affected bipolar, schizophrenia and substance abuse populations; and 2) to use advanced computational methods to determine the underlying genetic architecture of bipolar disease susceptibility in affected individuals, including the relative contributions of genetic heterogeneity and interactions.
The central hypotheses fueling my K08 application and my research more generally are that: a) shared and disease-specific genetic susceptibility to several neuropsychiatric disorders, at the population-level, is mediated by disruption of genes characterized by one or a limited combination of shared and discernible biological attributes, and b) the genetic architecture of these complex disorders is characterized by substantial inter-individual genetic heterogeneity. The hypothesis has been formulated on the basis of previous studies in complex genetic disorders, results and inconsistencies of previous neuropsychiatric research, as well as our own preliminary data. The rationale for the proposed research is that, first, uncovering the particular biological attributes defining susceptibility genes is likely to be of much greater significance to our understanding of disease and to future discovery efforts than any current single marker finding. Second, discovering the nature of the complex genetic architecture will inform valid models of genetic transmission and refinements of phenotypes upon which the design of future studies can be based. In so doing, it will also test the validity of the guiding assumptions about genetic risk in current neuropsychiatric genetic research. And third, together these results will make possible more targeted resequencing, fine-mapping and functional studies to uncover both the common and rare, as yet elusive, functional variants.