Project Summary

Andrew Makoff, Ph.D., BA (Independent Investigator 2002) of Institute of Psychiatry, will conduct a detailed examination of the region on chromosome 15 with the alpha 7 type of nicotine receptor gene (CHRNA7) to look for variations using DNA from patients with a major psychosis and from the general population.  He will look for gross structural variations such as the presence, absence and orientation of the partial duplication of CHRNA7 as well as small sequence changes.  Dr. Makoff believes that by finding a measurable characteristic which many schizophrenics share but which involves only one or a few genes may help with gene identification in schizophrenia.  This appears to be the case with an electrical measurement of brain activity.  In most normal people the response to the second of two identical sounds is smaller than the first, probably representing the ability of the brain to ignore repetitive or irrelevant sounds.  Schizophrenic patients often do not show this response pattern and neither do many of their close relatives.  Genetic and other studies have shown that much of this defect is due to a gene on chromosome 15 -- probably the CHRNA7.  Several other genetic studies have supported involvement of CHRNA7 in schizophrenia and in another psychiatric disorder, bipolar disorder.  Dr. Makoff has made a detailed analysis of this region using the results of the Human Genome Sequencing Project and has found evidence of complex duplication and an inversion of the duplicated part of CHRNA7.  However, not all humans have the partial duplication of CHRNA7, suggesting that the duplication occurred very recently in human evolution.  It is probable that there are also some humans who have an intermediate arrangement where the partial duplication of CHRNA7 is present but not inverted. The likely existence of these major structural variations in the present human population may be important in the involvement of this part of chromosome 15 in psychiatric disorders.  By performing a a variety of molecular studies to screen DNA from small groups of patients with schizophrenia and bipolar disorder and from unaffected patients, he will then compare the frequencies of novel genetic variants in a large well-characterized case/control sample.  Significant differences between cases and controls will indicate an association with the disorder.  Where significant associations are found, further variations will be sought nearby in the gene for more case/control frequency comparisons.  Successful identification of a predisposing variant(s) will be an important medical advance likely to result in improved diagnosis, treatment selection and to provide a target for designing new treatments.

Program Area: MULTIPLE FOCUS AREAS\Schizophrenia/Bipolar

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