DESCRIPTION (provided by applicant): Genetic analyses have highlighted the influence of >108 loci for cross-sectional schizophrenia (SZ), raising the hope of illuminating causative pathways and offering a rational approach to therapeutics. Complementing this effort, we have taken an orthogonal approach to enhance the detection of genes that might be relevant to specific subsets of patients with SZ. Through the intersection of biological insights gleaned from rare disorders with relevant neuropsychiatric co-morbidities and robust genetics, we and others have found that members of the pericentriolar material (PCM: centrosome, basal body, and primary cilium) are implicated in the pathogenesis of a subset of SZ characterized by neuroanatomical alterations in the cerebral cortex and/or resistance to antipsychotics. These findings form the foundation of our hypotheses that a) defining the consequences and mechanisms of ciliary/centrosomal dysfunction in vitro and in vivo will inform our understanding of the etiopathology of SZ; and b) sampling individuals with extreme phenotypes (i.e. resistant to treatment) will lead potentially to an enrichment of causal rare variants which would have otherwise not been observed or difficult to detect in a large, random sampling of SZ. To investigate these hypotheses, and to build on our previous observations, we will focus our study on establishing whether the loss of PCM1, an exemplar of ciliary biology and a loci associated with SZ, during discrete temporal and spatial periods of development is sufficient to drive neuroanatomical and behavioral deficits relevant to psychiatric disorders. In parallel, we will ask whether the treatment-resistant behavioral phenotypes observed in mutant mice and patients are related to perturbations in dopamine signaling and whether activation of downstream factors can circumvent the mislocalization of dopamine D2 receptor. Finally, we will sequence PCM1 in additional treatment-resistant cohorts and develop tools that enable the systematic interrogation of all candidate SZ alleles, in vivo. Completion of these studies will establish causality of a previously associated SZ loci and define whether perturbation of structural moieties such as the cilium during adolescence is associated with the pathomechanism of SZ.

PUBLIC HEALTH RELEVANCE Linking ciliary proteins to the pathomechanism of treatment-refractory schizophrenia will lead to a new module of gene candidates for contributing penetrance and expressivity alleles in humans, the identification of which will: a) improve exponentially our understanding of genetic load in humans; b) facilitate the clinical management of schizophrenia; and c) be potentially relevant to the pathogenesis of mental health disorders.