Project Summary

Russell Margolis, M.D. (Independent Investigator 2003) of Johns Hopkins University, notes that though genetic factors contribute to the risk of developing schizophrenia, the complexity of the disease and the probability that many genes and environmental factors influence vulnerability has hindered finding genetic risk factors. Using a strategy that has been successful in other complex diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), rare families in which disease results from a single mutation offer the chance to demonstrate biochemical pathways that can lead to the development of the disease, and offer opportunities to test therapeutic interventions. A similar situation now presents itself in schizophrenia. Dr. Margolis will study a large family in Scotland with a genetic rearrangement in which portions of chromosome 1 and 11 have switched positions. In the family, most individuals with the arrangement, but none without it, have developed schizophrenia or an affective disorder. The only gene altered by the genetic rearrangement (disrupted-in-schizophrenia-1 or DISC1) is expressed in areas of the brain implicated in schizophrenia, and is part of a large protein complex which includes NUDEL and LIS 1, in which each part appears to have a role in normal brain development—it’s possible that other mutations in these genes may lead to the more subtle developmental abnormalities associated with many cases of schizophrenia. Dr. Margolis will search for genetic mutations in DISC1, NUDEL, and LIS1 in a selected population of individuals with schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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