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. 2013 Jun 21:2013:bat046.
doi: 10.1093/database/bat046. Print 2013.

Analysis of disease-associated objects at the Rat Genome Database

Shur-Jen Wang  1 , Stanley J F Laulederkind, G T Hayman, Jennifer R Smith, Victoria Petri, Timothy F Lowry, Rajni Nigam, Melinda R Dwinell, Elizabeth A Worthey, Diane H Munzenmaier, Mary Shimoyama, Howard J Jacob
Affiliations

Analysis of disease-associated objects at the Rat Genome Database

Shur-Jen Wang et al. Database (Oxford). .

Abstract

The Rat Genome Database (RGD) is the premier resource for genetic, genomic and phenotype data for the laboratory rat, Rattus norvegicus. In addition to organizing biological data from rats, the RGD team focuses on manual curation of gene-disease associations for rat, human and mouse. In this work, we have analyzed disease-associated strains, quantitative trait loci (QTL) and genes from rats. These disease objects form the basis for seven disease portals. Among disease portals, the cardiovascular disease and obesity/metabolic syndrome portals have the highest number of rat strains and QTL. These two portals share 398 rat QTL, and these shared QTL are highly concentrated on rat chromosomes 1 and 2. For disease-associated genes, we performed gene ontology (GO) enrichment analysis across portals using RatMine enrichment widgets. Fifteen GO terms, five from each GO aspect, were selected to profile enrichment patterns of each portal. Of the selected biological process (BP) terms, 'regulation of programmed cell death' was the top enriched term across all disease portals except in the obesity/metabolic syndrome portal where 'lipid metabolic process' was the most enriched term. 'Cytosol' and 'nucleus' were common cellular component (CC) annotations for disease genes, but only the cancer portal genes were highly enriched with 'nucleus' annotations. Similar enrichment patterns were observed in a parallel analysis using the DAVID functional annotation tool. The relationship between the preselected 15 GO terms and disease terms was examined reciprocally by retrieving rat genes annotated with these preselected terms. The individual GO term-annotated gene list showed enrichment in physiologically related diseases. For example, the 'regulation of blood pressure' genes were enriched with cardiovascular disease annotations, and the 'lipid metabolic process' genes with obesity annotations. Furthermore, we were able to enhance enrichment of neurological diseases by combining 'G-protein coupled receptor binding' annotated genes with 'protein kinase binding' annotated genes. Database URL: http://rgd.mcw.edu

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Figures

Figure 1.
Figure 1.
The rat strain distribution among three RGD disease portals. The numbers in each area represent the strain count of that section. Strain names are available from the RGD disease portals (http://rgd.mcw.edu/wg/portals).
Figure 2.
Figure 2.
Cardiovascular and obesity diseases association of rat chromosome 2 and the human syntenies. Syntenic mapping of rat chromosome 2 to the human genome was performed using VCMap (http://animalgenome.org/VCmap/). (A) The two backbone chromosomes are labelled in Mbp. The chromosomal origins of syntenies are labelled to the right. (B) Rat and human syntenies are listed, with corresponding human orthologs for the rat syntenies, and disease-associated genes and QTL. (Asterisk) The cardiovascular and obesity diseases–associated genes (human and rat) and QTL (human) in the synteny were downloaded from ‘Disease Related Tracks’ (cardiovascular diseases and nutritional and metabolic diseases) from genome browsers at RGD. (rat: http://rgd.mcw.edu/fgb2/gbrowse/rgd_904/ and human: http://rgd.mcw.edu/fgb2/gbrowse/human_36_3/).
Figure 3.
Figure 3.
GO enrichment tables for the three GO aspects of genes associated with the obesity/metabolic syndrome portal. A total of 1049 rat genes associated with this disease portal were subjected to GO enrichment analysis in RatMine. Only the top portions of the enrichment tables are shown. Two GO terms selected from each GO aspect for comparison are highlighted.
Figure 4.
Figure 4.
(A) The BP annotations of the disease-associated genes at RGD were subjected to enrichment analysis using RatMine. The enrichment P-values, presented as ‘–Log P-value’ are shown in the top panel, and the percentages of genes annotated with the relevant GO term and its children are shown in the bottom panel. The six RGD disease portals—cancer portal (cancer), cardiovascular disease portal (cardiovascular), obesity/metabolic syndrome portal (ob/metabolic), respiratory disease portal (respiratory), immune and inflammatory disease portal (immune) and neurological disease portal (neurological)—are listed across the x axis. (B) The CC annotations of the disease-associated genes at RGD were subjected to enrichment analysis using RatMine. The enrichment P-values, presented as ‘–Log P-value’ are shown in the top panel, and the percentages of genes annotated with the relevant GO term and its children are shown in the bottom panel. The six RGD disease portals—cancer portal (cancer), cardiovascular disease portal (cardiovascular), obesity/metabolic syndrome portal (ob/metabolic), respiratory disease portal (respiratory), immune and inflammatory disease portal (immune) and neurological disease portal (neurological)—are listed across the x axis. (C) The MF annotations of the disease-associated genes at RGD were subjected to enrichment analysis using RatMine. The enrichment P-values, presented as ‘–Log P-value’ are shown in the top panel, and the percentages of genes annotated with the relevant GO term and its children are shown in the bottom panel. The six RGD disease portals—cancer portal (cancer), cardiovascular disease portal (cardiovascular), obesity/metabolic syndrome portal (ob/metabolic), respiratory disease portal (respiratory), immune and inflammatory disease portal (immune) and neurological disease portal (neurological)—are listed across the x axis.
Figure 4.
Figure 4.
(A) The BP annotations of the disease-associated genes at RGD were subjected to enrichment analysis using RatMine. The enrichment P-values, presented as ‘–Log P-value’ are shown in the top panel, and the percentages of genes annotated with the relevant GO term and its children are shown in the bottom panel. The six RGD disease portals—cancer portal (cancer), cardiovascular disease portal (cardiovascular), obesity/metabolic syndrome portal (ob/metabolic), respiratory disease portal (respiratory), immune and inflammatory disease portal (immune) and neurological disease portal (neurological)—are listed across the x axis. (B) The CC annotations of the disease-associated genes at RGD were subjected to enrichment analysis using RatMine. The enrichment P-values, presented as ‘–Log P-value’ are shown in the top panel, and the percentages of genes annotated with the relevant GO term and its children are shown in the bottom panel. The six RGD disease portals—cancer portal (cancer), cardiovascular disease portal (cardiovascular), obesity/metabolic syndrome portal (ob/metabolic), respiratory disease portal (respiratory), immune and inflammatory disease portal (immune) and neurological disease portal (neurological)—are listed across the x axis. (C) The MF annotations of the disease-associated genes at RGD were subjected to enrichment analysis using RatMine. The enrichment P-values, presented as ‘–Log P-value’ are shown in the top panel, and the percentages of genes annotated with the relevant GO term and its children are shown in the bottom panel. The six RGD disease portals—cancer portal (cancer), cardiovascular disease portal (cardiovascular), obesity/metabolic syndrome portal (ob/metabolic), respiratory disease portal (respiratory), immune and inflammatory disease portal (immune) and neurological disease portal (neurological)—are listed across the x axis.
Figure 5.
Figure 5.
(A) The disease enrichment analysis of five BP-annotated gene lists. The three most enriched diseases from each gene list are presented in Venn diagrams. The numbers in each area represent the gene count of the section. (B) The disease enrichment analysis of five CC-annotated gene lists. The three most enriched diseases from each gene list are presented in Venn diagrams. The numbers in each area represent the gene count of that section. (C) The disease enrichment analysis of five MF annotated gene lists. The three most enriched diseases from each gene list are presented in Venn diagrams. The numbers in each area represent the gene count of that section.
Figure 5.
Figure 5.
(A) The disease enrichment analysis of five BP-annotated gene lists. The three most enriched diseases from each gene list are presented in Venn diagrams. The numbers in each area represent the gene count of the section. (B) The disease enrichment analysis of five CC-annotated gene lists. The three most enriched diseases from each gene list are presented in Venn diagrams. The numbers in each area represent the gene count of that section. (C) The disease enrichment analysis of five MF annotated gene lists. The three most enriched diseases from each gene list are presented in Venn diagrams. The numbers in each area represent the gene count of that section.
Figure 6.
Figure 6.
Enhanced enrichment of neurological diseases by combining MF term–annotated gene lists. The ‘GPCR binding’ gene list was combined with the ‘protein kinase binding’ gene list or the ‘hormone activity’ gene list. The enrichment P-values for these two diseases, shown as ‘–Log P-value’ were compared before and after combination. The gene count of each list is shown in parenthesis.
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