Large-scale population genetic studies have begun to map the genetic architecture of schizophrenia (SZ). We now know that the genetic contribution of this multifactorial trait arises from a variety of lesions that include a) rare copy number variants (CNVs) of strong effect; b) common non-coding alleles of mild effect; and c) rare coding alleles that cluster in biological modules. Our recent studies have afforded us the opportunity to synthesize genetic, genomic, and functional studies to dissect the contribution of microtubule and ciliary dysfunction to SZ and to develop physiologically relevant assays to interrogate the effect of genes and alleles as a means of augmenting statistical power. Here, we will continue to focus on a specific biological module, the protein cluster that regulates microtubule function as it relates to axon/dendritic growth and ciliary function, and to dissect its contribution to SZ in terms of CNV pathomechanism; regulatory mutations; and rare alleles of large effect. We are uniquely placed to measure the contribution of this module to SZ. First, we will improve our understanding of the 16p11.2 CNV pathology, one of the most significant contributors to SZ; drawing from expertise both from our group as well as from Projects 2, 3 and Core C, we will test the contributory hypothesis for KCTD13, a gene for which we and others have amassed strong, but indirect, genetic and functional evidence of involvement. Second, we will assay the downstream effect of changes in four microtubule genes, including changes of regulatory elements, on the rest of the transcriptome and on SZ associated genes and pathways (with Project 2 and Core B). Finally, we will implement our in vivo assays to interpret sequencing data on candidate SZ genes in order to establish the direction of effect of candidate pathogenic alleles and to measure the overall burden of these loci to SZ. Taken together, our work, upon intersection with the studies of the other Center components, will inform the genetic contribution and the biological mechanisms of microtubule (dys)function to discrete aspects of SZ pathology and potentially help improve the design of treatment paradigms and future clinical trials.
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