Comparative Toxicogenomics Database: a knowledgebase and discovery tool for chemical-gene-disease networks

Abstract

The Comparative Toxicogenomics Database (CTD) is a curated database that promotes understanding about the effects of environmental chemicals on human health. Biocurators at CTD manually curate chemical-gene interactions, chemical-disease relationships and gene-disease relationships from the literature. This strategy allows data to be integrated to construct chemical-gene-disease networks. CTD is unique in numerous respects: curation focuses on environmental chemicals; interactions are manually curated; interactions are constructed using controlled vocabularies and hierarchies; additional gene attributes (such as Gene Ontology, taxonomy and KEGG pathways) are integrated; data can be viewed from the perspective of a chemical, gene or disease; results and batch queries can be downloaded and saved; and most importantly, CTD acts as both a knowledgebase (by reporting data) and a discovery tool (by generating novel inferences). Over 116,000 interactions between 3900 chemicals and 13,300 genes have been curated from 270 species, and 5900 gene-disease and 2500 chemical-disease direct relationships have been captured. By integrating these data, 350,000 gene-disease relationships and 77,000 chemical-disease relationships can be inferred. This wealth of chemical-gene-disease information yields testable hypotheses for understanding the effects of environmental chemicals on human health. CTD is freely available at http://ctd.mdibl.org.

Figure 1.

CTD curation and integration paradigm. (a) Biocurators capture three types of data from the literature for chemicals (C), genes (G) and diseases (D): C–G interactions, G–D relationships and C–D relationships. These three relationships generate a chemical–gene–disease triad. (b) The integration of these three data sets enables users to infer novel connections between chemicals–diseases and genes–diseases (dashed arrow).

Figure 2.

Discovering putative chemical–gene–disease networks for autism. The Chemical tab (red circle) on the CTD Disease page for Autistic Disorder displays chemicals (e.g. 4-hydroxymercuribenzoate) with an inferred connection to the disease based upon interaction with a gene already known to be associated with autism (e.g. PON1), allowing a putative, novel, chemical–gene–disease network to be proposed (insert). The cited reference (red box) will take the user to a page that provides a link to the curated interactions between 4-hydroxymercuribenzoate and PON1 as well as the reference describing the PON1–Autistic Disorder relationship.

Figure 3.

CTD Chemical page for bisphenol A. CTD uses tabs to organize data. The Basic Information tab provides names, synonyms, identification numbers, structures, a graph of the top 10 interacting genes and the chemical hierarchy. The Gene tab shows all 455 genes that interact with bisphenol A, the number of curated interactions between the chemical and gene, and the number of unique organisms for which an interaction has been curated. The Interactions tab displays the 655 detailed molecular interactions between bisphenol A and those 455 genes. The table is divided into columns for Interacting Chemical, Interacting Gene, Organism, Interaction and Reference. Columns can be sorted by clicking on their headers. All chemicals, genes, interactions, references and diseases (data not shown) are hyperlinked to their respective CTD pages, allowing the user to navigate integrated data. Complete data pages can be downloaded and saved as CSV, XML or TSV files onto the user's desktop by using the ‘Save to File’ function at the bottom of the page. The keyword search box is seen in the upper right corner of the bisphenol A Chemical page.