This is a small grant program application for an exploratory study by two senior investigators. New molecular genetic approaches to identify genes contributing to the development of affective disorders will be piloted in an existing population of childhood onset major depressive disorder and bipolar affective disorder probands. Earlier age of onset of both major depressive disorder (MDD) and bipolar affective disorder has been associated with increased familiality in studies of pedigrees identified through adults, adolescents and children. Modeling studies suggest that the distribution of illness in the relatives of early onset affective disorder patients is most compatible with the presence of major gene effects. Hence, the power of studies aimed at identifying specific genetic factors in the development of serious affective disorders should, according to the applicant, be increased by the use of child probands. In this exploratory study, the applicant proposes to sample cohorts from a prospective, blindly rated, controlled study of prepubertal major depressive disorder and test for the contribution of candidate genetic loci identified in studies of adult disorders to the development of child illness. DNA samples from 70 childhood onset affective disorder probands and their biological parents will be collected. These samples (n=210) will be genotyped for five loci which have been implicated in the development of affective disorders in studies of adult probands. Using recently described haplotype relative risk analyses, these data will be tested for the presence of significant genetic associations. This pilot study will evaluate the feasibility and appropriateness of sampling families through childhood onset probands and will serve as a replication study for reports in the adult literature. If successful, these approaches will then be applied to larger, ongoing studies of early onset affective disorders.
