CHDbase: A Comprehensive Knowledgebase for Congenital Heart Disease-related Genes and Clinical Manifestations

Abstract

Congenital heart disease (CHD) is one of themost common causes of major birth defects, with a prevalence of 1%. Although an increasing number of studies have reported the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase of CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of studies were integrated with each item of the research record. We also integrated functional annotations through parsing ∼ 50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibilities, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org.

Keywords: Classification; Congenital heart defect; Congenital heart disease; Database; Genetics.

Figure 1

Overview of the framework of CHDbase CHD, congenital heart disease; SNV, single nucleotide variant; Indel, insertion-deletion variant; CNV, copy number variation; ID, identity document; HGVSc, the Human Genome Variation Society expressions at the cDNA level; HGVSp, the Human Genome Variation Society expressions at the protein level; PTM, posttranslational modification; GO, Gene Ontology; MAF, minor allele frequency.

Figure 2

Network-based prioritization of CHD-related genes A. The k-core of CHD-related genes (n = 163). The node size is proportional to the number of supporting evidence items for each gene. B. For 18 core genes overlapping with the high-confidence CHD genes recurrently reported in recent reviews, the degree, betweenness centrality, eigenvector centrality, and the number of supporting evidence items for each gene are listed.

Figure 3

The web interface of CHDbase The major components of the web interface of CHDbase are shown. A. The navigation bar. B. The Home Page. C. The Browse Page. D. The Evidence and Annotation Page for each CHD-related gene or variation. E. The Statistics Page for the diseases, genes, variations, and studies. F. The Help Page.

Figure 4

The expression profiles of CHD-related genes A. and B. Boxplots showing the expression levels for three categories of CHD-related genes in the brain (A) and heart (B) across different developmental time points. C. and D. Violin plot showing the difference between CHD-related genes and background genes in tissue-specificity (C) and time-specificity (D). The P values were obtained with Mann–Whitney U test. In all panels, CHD-related genes are classified into three categories: syndromic genes (red, n = 115), nonsyndromic genes (blue, n = 597), and genes reported in both syndromic and nonsyndromic CHD (orange, n = 414). A non-CHD gene set (n = 1124) was randomly selected as the background (gray). TPM, transcripts per million; PCW, post-conception week.

Figure 5

Functional enrichments of CHD-related genes A. The top 15 significantly enriched GO terms for CHD-related genes (n = 1124) are shown with significance levels. B. The top 15 significantly enriched KEGG and Reactome pathways for CHD-related genes (n =1124) are shown with significance levels. The adjusted P values corrected with Bonferroni step down were – log₁₀ transformed to denote the significance levels. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; TCF, T-cell factor; Wnt, wingless-type MMTV integration site family; GFR, growth factor receptor.

Figure 6

CHD classification based on genotype–phenotype correlations A. Jaccard coefficient, Jaccard distance, statistical significance for Jaccard coefficient, and gene distribution are shown for 20 pairs of CHD types with the strongest correlations. The centered Jaccard coefficient equals to the Jaccard coefficient minus the unbiased estimation of expectation. P and Adjusted P were calculated with the Jaccard test and corrected for multiple testing using the Benjamini–Hochberg false discovery rate. B. Classification of 27 CHD types in CHDbase. Only CHD types associated with at least ten genes were included in this analysis. Jaccard distances for all pairs of CHD types are shown in a heatmap, which were further used to classify these CHD types into seven major groups through hierarchical cluster analysis. For each group, the anatomical term is defined and shown. POF, patent oval foramen; PDA, patent arterial duct; PS/PVS, pulmonary stenosis/pulmonary valve stenosis; BAV, bicuspid aortic valve; AS/AVS, aortic stenosis/aortic valvar stenosis; AR, aortic regurgitation; MR, mitral regurgitation; SV, single ventricle; PA, pulmonary atresia; Dxc, dextrocardia; APVC, anomalous pulmonary venous connection; CoA, coarctation of the aorta; VCAb, vena cava abnormality; TA, tricuspid atresia; TR, tricuspid regurgitation; EA, Ebstein malformation of the tricuspid valve; TOF, tetralogy of Fallot; OA, overriding aorta; cAVJ, common atrioventricular junction; AVSD, atrioventricular septal defect; VSD, ventricular septal defect; ASD, atrial septal defect; DORV, double-outlet right ventricle; TGA, transposition of the great arteries; PTA, persistent truncus arteriosus; RAA, right aortic arch; IAA, interrupted aortic arch; RVOTO, right ventricular outflow tract obstruction; LVOTO, left ventricular outflow tract obstruction.

Supplementary Figure S1

Chromosome distribution for CHD-related genes The color of each gene represents the type of evidence supporting the association of the gene with CHD. The shape of each gene represents the category of the gene.

Supplementary Figure S2

Typical Gene Evidence Page and Annotation Page in CHDbase The Gene Evidence Page displays the evidence details at the gene level. Gene annotations can be obtained by clicking on the label “Gene Annotation” in the top left.

Supplementary Figure S3

Examples of evidence details at the gene level As shown in Figure S2, the evidence list is shown in the upper panel of the Gene Evidence Page, and the details of the evidence are shown in the lower panel. In the lower panel, population information, study design, and result summary are provided at the top for all types of evidence, and result details are provided in the lower part in different formats for different types of evidence.

Supplementary Figure S4

Typical Variation Annotation Page in CHDbase