2/3: Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders

University Of Texas Rio Grande Valley, Edinburg TX

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Abstract

PROJECT SUMMARY The Whole Genome Sequencing of Psychiatric Disorders (WGSPD) consortium requests administrative supplements for the 11 constituent grants comprising its four projects. The supplements will support additional work, planned and performed in an integrated way by the consortium as a whole, to advance the primary goal of WGSPD: elucidating the full genetic architecture underlying susceptibility to severe mental disorders (SMD). It is now clear that current rare-variant association studies are underpowered for the confident identification of variants with a substantial impact on SMDs. As the WGSPD recently reported (Sanders et al. 2017 [PMID:29184211]), the consortium efforts to date in four main categories represent an important step in improving the power of WGS studies: (1) implementing common pipelines to enable cross-project sequence analysis; (2) harmonizing phenotype data to facilitate cross-disorder analyses with the largest possible samples, and employing phenotype constructs hypothesized to be more precise than syndrome diagnoses; (3) employing a diversity of study designs and analysis methods to boost the possibility of detecting novel high-impact variants; (4) conducting experimental (functional genomic) and bioinformatics studies that will allow us to reduce the search space for association analysis of non-coding variants from the entire genome to a smaller number of regions prioritized based on biological function. The WGSPD consortium now seeks to further enhance the opportunity to identify genetic variants contributing to SMDs by completing two supplement aims, which we believe will enable us to further increase the power of rare-variant analyses of coding and non-coding sequences. Both supplement aims are consistent with the scope of the original awards and prior supplements (in the four major areas noted above), but leverage samples, methods, and data that have only recently become available to the WGSPD. These aims are to: 1) increase the impact of WGSPD rare-variant genetic analyses by increasing the sample size available for analyses, enhancing the utility of the phenotype data available, and conducting improved genetic analyses and 2) extend WGSPD functional genomic and bioinformatic analyses to improve prioritization of non-coding regions and variants.