Schizophrenia (SZ) is a complex genetic disorder with a lifetime risk of approximately 1%. Recent technological innovations have opened a new window into the genetic basis of SZ. Based on work by multiple groups using different approaches to examine genome-wide association (GWA), and the association of copy number variants (CNVs) and single nucleotide polymorphisms (SNPs) with SZ, multiple risk factors have been definitively identified. They can now be studied experimentally to understand their molecular and neurobiological effects. These risk factors include individually-rare mutations that confer high risk as well as common genetic variants that confer modest effects. Here, we hypothesize that defects in multiple genes that are diverse in their individual functions, but interact within the context of cellular pathways are important for SZ pathogenesis. To test this hypothesis, we propose to investigate SZ from the """"""""systems biology"""""""" perspective with the aim of defining protein interaction networks and functional modules that are relevant to the disease. To achieve this goal, we propose an integrative approach to build SZ protein-protein interaction network (i.e. SZ interactome) that includes SZ risk genes, their brain splice variants and mutant transcripts of the genes that are disrupted by the breakpoints of genomic deletions and duplications in SZ patients.
The specific aims are as follows. (1) Perform a large-scale discovery of brain alternatively spliced isoforms of SZ gene candidates using our recently developed high-throughput isoform discovery pipeline that incorporates parallel 454 FLX sequencing and computational analysis platforms;(2) Identify and clone mutant transcripts of the genes disrupted by the breakpoints of genomic deletions and duplications in SZ patients;(3) Build an interactome of SZ candidate genes, their alternatively spliced variants and mutant transcripts to define key functional modules involved in SZ pathology. The results of this study will make substantial contributions to knowledge of the cellular pathways that underlie schizophrenia.

Public Health Relevance

The results of this study will make substantial contributions to our knowledge of the causes of schizophrenia and of cognitive development. The discovery of functional modules that connect schizophrenia candidate genes, their splice variants and mutants is an important step towards understanding the mechanism of disease development. The final goal of this project is to define specific schizophrenia-relevant protein interactions that could be targeted therapeutically.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Senthil, Geetha
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University of California San Diego
Schools of Medicine
La Jolla
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Yang, Xinping; Coulombe-Huntington, Jasmin; Kang, Shuli et al. (2016) Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 164:805-17
Lin, Guan Ning; Corominas, Roser; Lemmens, Irma et al. (2015) Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases. Neuron 85:742-54
Dembinski, Holly; Wismer, Kevin; Balasubramaniam, Deepa et al. (2014) Predicted disorder-to-order transition mutations in I?B? disrupt function. Phys Chem Chem Phys 16:6480-5
Rolland, Thomas; Ta?an, Murat; Charloteaux, Benoit et al. (2014) A proteome-scale map of the human interactome network. Cell 159:1212-1226
Corominas, Roser; Yang, Xinping; Lin, Guan Ning et al. (2014) Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nat Commun 5:3650
Braff, Lara; Braff, David L (2013) The neuropsychiatric translational revolution: still very early and still very challenging. JAMA Psychiatry 70:777-9
Braff, David L; Ryan, James; Rissling, Anthony J et al. (2013) Lack of use in the literature from the last 20 years supports dropping traditional schizophrenia subtypes from DSM-5 and ICD-11. Schizophr Bull 39:751-3
Vacic, Vladimir; Iakoucheva, Lilia M (2012) Disease mutations in disordered regions--exception to the rule? Mol Biosyst 8:27-32
Michaelson, Jacob J; Shi, Yujian; Gujral, Madhusudan et al. (2012) Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151:1431-42
Vacic, Vladimir; Markwick, Phineus R L; Oldfield, Christopher J et al. (2012) Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder. PLoS Comput Biol 8:e1002709

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