This is an application for a 5-year Mentored Clinical Scientist Development Award (K08). The candidate has received training in human genetics and additional trainingin psychiatry. The goal for this award is to develop the candidate's skills in gene mappingof complex traits, such as psychiatric disorders, using symptom dimensions and neurophysiologicallydefined endophenotypes as traits. During the time of the award, the candidate will acquire knowledge in the applicationof newly developed statistical methods to address the problem of clinical heterogeneity in patient samples with psychoticdisorders. Understandingthe heterogeneity in these disorders is one of the major challenges in the attempt to identify underlying genetic mutations. Defining the differences in clinical symptoms and neurophysiologicfunctioning is therefore of utmost importance. Several recent findings suggest that this approach to gene identificationis useful. The long-term aim of the candidate is to understand the cognitive, emotional, behavioral andneurophysiologic abnormalities of psychotic disorders, their overlaps and their differences and to link these to molecular abnormalities. This may, if successful, enhance the understanding of these disorders and improve diagnostics and treatment. The training goal will be reached using the following steps: 1.A combination of factor analysis and latent class analysis (factor mixture model) will be used to subgroup patients from the NIMH schizophrenia and bipolar genetics initiatives.2. Linkage analysis and quantitativetrait locus mappingwill be performed on these so defined subgroups.3. Experience in the use of endophenotypes for genetic studieswill be obtained throughparticipationin ongoing studies at UCLA. The NeuropsychiatricInstitute at UCLA provides the ideal environment for this proposal. The mentorship of Dr. Nelson Freimer, Dr.Andrew Leuchter and Dr. Bengt Muthen, who are all experts in overlappingaspects of this proposal, will guarantee the success of the training,complemented by coursework and conferences.
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