An integrative tissue-network approach to identify and test human disease genes

Abstract

Effective discovery of causal disease genes must overcome the statistical challenges of quantitative genetics studies and the practical limitations of human biology experiments. Here we developed diseaseQUEST, an integrative approach that combines data from human genome-wide disease studies with in silico network models of tissue-and cell-type-specific function in model organisms to prioritize candidates within functionally conserved processes and pathways. We used diseaseQUEST to predict candidate genes for 25 different diseases and traits, including cancer, longevity, and neurodegenerative diseases. Focusing on Parkinson's disease (PD), a diseaseQUEST-directed Caenhorhabditis elegans behavioral screen identified several candidate genes, which we experimentally verified and found to be associated with age-dependent motility defects mirroring PD clinical symptoms. Furthermore, knockdown of the top candidate gene, bcat-1, encoding a branched chain amino acid transferase, caused spasm-like 'curling' and neurodegeneration in C. elegans, paralleling decreased BCAT1 expression in PD patient brains. diseaseQUEST is modular and generalizable to other model organisms and human diseases of interest.

High-throughput behavioral screen inC. elegansreveals novel Parkinson’s disease drug candidates

“…We found that BCAT1 expression is decreased in PD patient substantia nigra, and reduction of bcat-1 in C. elegans promotes dopaminergic neurodegeneration 5 . Moreover, RNAi-mediated knockdown of bcat-1 in C. elegans causes age-dependent spasm-like 'curling' behavior, serving as a new model for PD motor symptoms 5 .…”

“…Currently, there is no cure for PD and treatment options only mitigate symptoms without modifying the course of the disease 4 . Using diseaseQUEST, our recently developed tissue-network approach to identifying and testing new candidates for human disease genes, we discovered a novel link between branched-chain amino acid transferase 1 (BCAT1) and PD 5 . We found that BCAT1 expression is decreased in PD patient substantia nigra, and reduction of bcat-1 in C. elegans promotes dopaminergic neurodegeneration 5 .…”

“…Using diseaseQUEST, our recently developed tissue-network approach to identifying and testing new candidates for human disease genes, we discovered a novel link between branched-chain amino acid transferase 1 (BCAT1) and PD 5 . We found that BCAT1 expression is decreased in PD patient substantia nigra, and reduction of bcat-1 in C. elegans promotes dopaminergic neurodegeneration 5 . Moreover, RNAi-mediated knockdown of bcat-1 in C. elegans causes age-dependent spasm-like 'curling' behavior, serving as a new model for PD motor symptoms 5 .…”

Association Study based on Topological Constraints of Protein-Protein Interaction Networks

“…The first limitation is the incompleteness of the resources including the interactomes, the coverage of genes in different gene sets, and gene annotations in GO or pathway knowledge databases. In addition, protein-protein interactions are dynamic , and they may vary significantly among different tissues or cell types (Ellis et al 2012;Yao et al 2018). These limitations may be addressed in future studies by the integration of tissue-specific or celltype-specific interactomes to further our understanding of the biological significances of different gene sets.…”

Metabolic defects cause hyperactive mitochondria and Parkinson’s disease-like traits

“…In an effort to identify novel PD genes, we recently developed diseaseQUEST, a method that combines human genome-wide association studies with tissue-specific functional genetic networks and high-throughput behavioral screening in C. elegans 2 . Using this computational-experimental framework, we discovered a novel link between branched-chain amino acid transferase 1 (BCAT-1), which catalyzes the first step in branched-chain amino acid (BCAA) catabolism 9 , and PD.…”