This is the third submission of this R01 proposal.
The aims of this proposal are to perform a genomewide scan looking for linkage to a schizophrenia-associated endophenotype, an elevated frequency of leading saccades during a smooth pursuit eye movement (SPEM) task. SPEM abnormalities have been associated with schizophrenia for almost 100 years, and have been suggested as a potential marker of genetic risk for schizophrenia for over 20 years. Over the last several years, we have focused on identifying the component(s) of SPEM most specific to schizophrenia and most sensitive to presumed genetic risk. An elevated frequency of leading saccades during a SPEM task appears to be a sensitive and specific component of SPEM function. Elevated frequency of leading saccades is more common in individuals with schizophrenia than in the general population or in individuals with attention deficit/hyperactivity disorder, autism, or bipolar disorder; is more common in relatives of individuals with schizophrenia; appears to sort with presumed genetic risk for schizophrenia; and is usable from 6-80 years of age. Additionally, elevated leading saccade frequency is tri-modally distributed in the general population, has a similar variance in normal and affected populations, and segregates in families with schizophrenia in a manner consistent with a major gene effect. These findings suggest that this phenotypc is appropriate for linkage analysis. To increase the homogeneity and genetic loading of the sample, two approaches will be used.
First (aim #1), extended pedigrees will be gathered from multi-affected families (2 or more family members with schizophrenia).
Second (aim #2), increased genetic loading will be sought by utilizing families in which the schizophrenic probands have very early ages of onset, at age 12 years or younger. Linkage in both groups will assessed using methods capable of detecting genetic effects on quantitative traits.
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