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Cell Type-Specific Proteogenomic Signal Diffusion for Integrating Multi-Omics Data Predicts Novel Schizophrenia Risk Genes

27 Pages Posted: 3 Jun 2020 Publication Status: Published

See all articles by Abolfazl Doostparast Torshizi

Abolfazl Doostparast Torshizi

University of Pennsylvania - Children's Hospital of Philadelphia

Jubao Duan

North Shore University Health System - Center for Psychiatric Genetics

Kai Wang

University of Pennsylvania - Department of Pathology and Laboratory Medicine; Children’s Hospital of Philadelphia - Raymond G. Perelman Center for Cellular and Molecular Therapeutics

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Abstract

Accumulation of diverse types of omics data on schizophrenia (SCZ) requires a systems approach to jointly modeling the interplay between genome, transcriptome and proteome. Proteome dynamics, as the definitive cellular machinery in human body, has been lagging behind the research on genome/transcriptome in the context of SCZ, both at tissue and single-cell resolution. We introduce a Markov Affinity-based Proteogenomic Signal Diffusion (MAPSD) method to model intra-cellular protein trafficking paradigms and tissue-wise single-cell protein abundances. MAPSD integrates multi-omics data to amplify the signals at SCZ risk loci with small effect sizes, and reveal convergent disease-associated gene modules in the brain interactome as well as more than 130 tissue/cell-type combinations. We predicted a set of high-confidence SCZ risk genes, the majority of which are not directly connected to SCZ susceptibility risk genes. We characterized the subcellular localization of proteins encoded by candidate SCZ risk genes in various brain regions, and illustrated that most are enriched in neuronal and Purkinje cells in cerebral cortex. We demonstrated how the identified gene set may be involved in different developmental stages of the brain, how they alter SCZ-related biological pathways, and how they can be effectively leveraged for drug repurposing. MAPSD can be applied to other polygenic diseases, yet our case study on SCZ signifies how tissue-adjusted protein-protein interaction networks can assist in generating deeper insights into the orchestration of polygenic diseases.

Keywords: Data Integration, Signal Diffusion, Complex Diseases, Graph Theory

Suggested Citation

Doostparast Torshizi, Abolfazl and Duan, Jubao and Wang, Kai, Cell Type-Specific Proteogenomic Signal Diffusion for Integrating Multi-Omics Data Predicts Novel Schizophrenia Risk Genes. Available at SSRN: https://ssrn.com/abstract=3600562 or http://dx.doi.org/10.2139/ssrn.3600562
This version of the paper has not been formally peer reviewed.

Abolfazl Doostparast Torshizi

University of Pennsylvania - Children's Hospital of Philadelphia

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Jubao Duan

North Shore University Health System - Center for Psychiatric Genetics ( email )

Kai Wang (Contact Author)

University of Pennsylvania - Department of Pathology and Laboratory Medicine ( email )

United States

Children’s Hospital of Philadelphia - Raymond G. Perelman Center for Cellular and Molecular Therapeutics ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

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