AbstractTo further our efforts in identifying the molecular bases of bipolar disorder and schizophrenia, we propose to studyprotein translation and abundances at the genome-wide level in frontal cortex tissue from 300 brains from patientsand healthy controls. We have already amassed an enormous amount of data from these brains, includinggenotypes, transcriptome profiles and chromatin states. The next step is to look for alterations in protein function inthe same brains, since proteins are the ultimate products of gene expression and a critical link between geneticvariants and higher order phenotypes, including disease diagnosis. Since proteins are encoded by mRNAtranscripts, it appears that protein levels should roughly correlate with transcript levels. However, measuredexpression levels of mRNAs and their corresponding proteins are often discordant, as are maps of their respectivequantitative trait loci. Since we are unable to explain these discrepancies, our picture of molecular changesunderlying psychiatric disorders is clearly incomplete.Most previous population-based studies of proteins in neuropsychiatry have been limited to candidate proteins, forwhich antibodies are already available. For example, in our PsychENCODE project, we are the process of usingmicrowestern arrays to assay ~1000 proteins. In this study, we will use the recently developed technique ofribosome profiling and next-generation proteomics to identify which transcripts are actively being translated in brainand to quantify the abundance of more than 12,000 proteins. Through integrative data analysis, we use the twocomplementary technologies to detect translational products and to measure their quantitative relationships.Furthermore, these proteins and their translation efficiencies will be assessed for association with disorders. Tofurther improve the specificity of quantification, we will use state-of-the-art deconvolution methods to quantify celltype specific measures of translation efficiency and protein products. This will allow protein translation andabundance in specific major brain cell types to be studied for their changes in affected brains.This study is innovative for being the first genome-wide, population-based study of protein translation andabundance in brains of psychiatric patients. It offers a unique opportunity to fill the gaps between transcriptome andproteome data, and between genetic variants and higher-order phenotypes. It will be a huge step forward instudying the proteins of human brains and the regulatory changes associated with psychiatric disorders, whichshould ultimately lead to better diagnosis and treatment of these diseases.
|Effective start/end date||7/8/16 → 4/30/20|
- National Institutes of Health: $517,845.00