Developing mechanistic models of how risk genes for schizophrenia and related developmental disorders influence brain function is the critical next step in the development of better prediction of risk and in treatment.

Molecular mechanisms of genetic risk

The tremendous advances in identifying genomic regions associated with psychiatric disorders has provided the first objective clues to basic causative mechanisms and etiology. Successful utilization of these clues will require a detailed understanding of which of the associated genetic variants are functional, which genes they influence, and how such changes in gene expression and biology affect brain function.

The Functional Genomics group integrates information about DNA variation and RNA expression with cellular, neuroimaging, cognitive, and clinical phenotypes to find specific genotype-expression-phenotype connections. These connections are then used to create testable molecular models of genetic risk. We start with DNA clinical risk variants and their association with the expression of specific RNA splice variants, or isoforms, to identify which isoforms are most strongly associated with disease risk and state. From this knowledge, we design cellular (in vitro) and animal (in vivo) models based on manipulation of gene expression to critically explore in detail the functional consequences of such gain or loss or alteration of function in the brain. Building a catalog of the downstream biochemical, electrophysiological, transcriptome, and behavioral consequences of the dysfunction downstream of many different risk genes will generate the understanding of the important pathways necessary for an evidence-based search for molecular targets for therapeutic intervention.

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Collaborators

The Lieber Institute has developed collaborations with academic institutions, pharmaceutical companies, government agencies and other private research institutions around the globe.
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