Modeling Dimensionality and Genetic Heterogeneity in Schizophrenia



 DESCRIPTION (provided by applicant): Schizophrenia (SZ) represents a significant and costly public health burden. Recently, we have witnessed the emergence of the first molecular insights into the etiopathogenic mechanisms of SZ, via the first genome-wide association studies (GWAS) with sufficient case-control sample sizes to detect allelic effects. Importantly, a polygenic signature, which includes genome-wide significant common genetic variants of small effect, has been clearly demonstrated to influence SZ risk. The availability of well-defined risk factors makes it possible, for the first time, to address several critical questions about the genetic architecture of SZ and its component phenotypes and endophenotypes. The overarching goals of this K01 proposal are 1) to test polygenic risk score prediction of dimensional SZ and schizotypy phenotypes across large case, high-density SZ pedigree, and prodromal-aged GWAS samples, and 2) to develop and test, with leaders of the Psychiatric Genomics Consortium, innovative statistical methods to identify and characterize "genetic subtypes" of SZ. This proposal delineates a series of training and research goals for the candidate that incorporates strengths from phenotypic assessment, statistical genetics, and molecular genetics and combines samples reflecting a broad range of genetic risk. The candidate will capitalize on previously established expertise in schizotypy and clinical risk assessment, as well as expertise in the familial transmission of dimensional traits, to establish a program of translational research wherein the application of statistical genetic/bioinformatic techniques to genetic subtyping analyses will be used to generate promising candidates for further exploration in human genomic data. Empirically-based genetic subtyping methods will be developed and tested in the largest SZ case sample to date, and subtypes will be characterized with respect to dimensional phenotypic traits. Top loci hits in subtype analyses of dimensional symptoms will be validated in secondary analyses of differential gene expression in post-mortem SZ brain. This will allow for a detailed analysis of function at both the SNP and gene levels, and will provide the candidate with substantive training in both statistical and molecular genetics methods. The institutional environment is ideal for the candidate's goal of developing a comprehensive program in SZ research, and the proposed research represents an important contribution toward advancing the understanding of SZ through a combination of clinical, statistical, molecular, and translational methods, consistent with the mission of the NIMH.