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Part 2: Preparing the enrichment libraries

2024-07-08

This part deals with the scripts that are used to download associations of genes to adverse effects, diseases, pathways and other relevant phenotypes to build gene set libraries that are used for performing enrichment analysis or for calculating proximity within our framework. Here, library refer to a group of gene sets. The libraries are stored as R named list with list element being the gene sets. The genes are represented by their Ensembl IDs.

2.1. Retrieving the databases for curating the disease and adverse effect gene sets

Rscript

Scripts/Enrichment_analysis_libraries/Enrichment_Analysis_Libraries_ADR.R

Scripts/Enrichment_analysis_libraries/Enrichment_Analysis_Libraries_Diseases.R
Input

  • ADRAlert2GENE2ID.xlsx (ADReCS)

  • curated_gene_disease_associations.tsv.gz (DisGeNet)

  • associationByDatatypeDirect (Open Targets)

  • IntOGen-Drivers-20230531.zip (Intogen)

  • Disease_Signatures_from_GEO_up_2014.txt (Enrichr)

  • relationships.zip (PharmGKB)

  • CTD_genes_diseases.csv.gz (Comparative Toxicogenomics Database)
Output

  • ADReCS_ADR2Gene_level4_lib.rds

  • ADReCS_ADR2Gene_level3_lib.rds

  • DisGeNET_Disease2Gene_lib.rds

  • DisGeNET_Phenotype2Gene_lib.rds

  • DisGeNET_DiseaseGroup2Gene_lib.rds

  • OpenTargets_Disease2Gene_GA_lib.rds

  • OpenTargets_Disease2Gene_RNA_lib.rds

  • OpenTargets_Disease2Gene_lit_lib.rds

  • OpenTargets_Disease2Gene_SM_lib.rds

  • Intogen_Disease2Gene_lib.rds

  • Enrichr_Disease2Gene_GeoDiseaseSig_lib.rds

  • PharmGKB_Disease2Gene_lib.rds

  • CTD_Disease2Gene_lib.rds
Summary The scripts retrieves associations of genes to adverse effect and diseases as curated in different databases. Where ever possible, the types or the sources of the associations have been segregated and are stored separately.

2.2. Preparing disease specific libraries

Rscript

Scripts/Enrichment_analysis_libraries/Disease2Gene_BreastCancer_lib.R

Scripts/Enrichment_analysis_libraries/Disease2Gene_KidneyCancer_lib.R

Scripts/Enrichment_analysis_libraries/Disease2Gene_LungCancer_lib.R

Scripts/Enrichment_analysis_libraries/Disease2Gene_OvaryCancer_lib.R

Scripts/Enrichment_analysis_libraries/Disease2Gene_ProstateCancer_lib.R

Scripts/Enrichment_analysis_libraries/Disease2Gene_SkinCancer_lib.R
Input

  • DisGeNET_Disease2Gene_lib.rds

  • OpenTargets_Disease2Gene_GA_lib.rds

  • OpenTargets_Disease2Gene_RNA_lib.rds

  • OpenTargets_Disease2Gene_lit_lib.rds

  • OpenTargets_Disease2Gene_SM_lib.rds

  • Enrichr_Disease2Gene_GeoDiseaseSig_lib.rds

  • Intogen_Disease2Gene_lib.rds

  • PharmGKB_Disease2Gene_lib.rds
Output

  • Disease2Gene_BreastCancer_lib.rds

  • Disease2Gene_KidneyCancer_lib.rds

  • Disease2Gene_LungCancer_lib.rds

  • Disease2Gene_OvaryCancer_lib.rds

  • Disease2Gene_ProstateCancer_lib.rds

  • Disease2Gene_SkinCancer_lib.rds
Summary The scripts prepares six cancer type specific gene set libraries using the gene disease associations retrieved in section 2.1.

2.3. Prepare the adverse effect linked gene set library

Rscript Scripts/Enrichment_analysis_libraries/Enrichment_Analysis_Libraries_curatedADR.R
Input

  • ADReCS_ADR2Gene_level3_lib.rds

  • ADReCS_ADR2Gene_level4_lib.rds

  • CTD_Disease2Gene_lib.rds

  • DisGeNET_Disease2Gene_lib.rds

  • DisGeNET_DiseaseGroup2Gene_lib.rds

  • DisGeNET_Phenotype2Gene_lib.rds
Output

  • curatedAdr2Gene_lib.rds

  • curatedAdr2Gene_libInfo.xlsx
Summary The script curates gene set library with the genes linked to adverse drug reactions that are frequently associated with drug withdrawal from the market and other relevant organ toxicities. The script also calculates the Jaccard similarity between the gene sets in this library,

2.4. Retrieving and prepare pathway related gene set libraries

Rscript Scripts/Enrichment_analysis_libraries/Enrichment_Analysis_Libraries_Pathways.R
Input

  • PMC7013921/Table_1.xls (PubMed Central)

  • smpdb_proteins.csv.zip (SMPDB)

  • smpdb_pathways.csv.zip (SMPDB)
Output

  • CHG_keggPath2Gene_lib.rds

  • SMPDb_Pathway2Gene_lib.rds
Summary The script curates two library consisting of pathways from two different sources. The first library consists of cancer hallmark associated KEGG pathways. The list of characteristic KEGG pathways of different cancer hallmarker were retrieved from the research article PMC7013921 while the genes in the KEGG pathway were sourced from the KEGG database. The second library is based on the pathways curated in the Small Molecule Pathway Database (SMPDB). The library consists of two sub-libraries — one for the pathways associated to drug action while the other for pathways linked to drug metabolism.

2.5. Retrieve and prepare library consisting of miscellaneous gene sets

Rscript Scripts/Enrichment_analysis_libraries/Enrichment_Analysis_Libraries_Miscellaneous.R
Input

  • categories.tsv (DGIdb)

  • genes.zip (PharmGKB)

  • human_genes.zip (GenAge)

  • suppl_data_baaa045.zip (PubMed)
Output miscellaneous_gene_lib.rds
Summary

The script curates a library by combining four independent gene sets — genes in drugable geneome from Drug Gene Interaction Database (DGIdb), very important pharmacogenes from PharmGKB, genes related to ageing from GenAge database and hallmarkers of cancer (HOC) genes from HOC database.

Note: To compile the HOC genes, the supplementary file ‘Halifax-curation.Table S2. Hallmark of Cancer Data - Gene and Pathway.xlsx’ must be manually downloaded from the research article PMC7294774 and placed inside the Databases/HOCdb/ directory.