IDSL.GOA: Gene Ontology Analysis for Metabolomics.

Biological interpretation of metabolomics datasets often ends at a pathway analysis step to find the over-represented metabolic pathways in the list of statistically significant metabolites. However, definitions of biochemical pathways and metabolite coverage vary among different curated databases, leading to inaccurate and contradicting interpretations. For the lists of gene, transcripts and proteins, Gene Ontology (GO) terms over-presentation analysis has become a standardized approach for the biological interpretation. GO terms are not limited to predefined pathways but can also include relevant metabolic processes that are not included in pathway databases. Despite the several advantages of GO terms over traditional pathway maps, GO analysis has not been achieved for metabolomics datasets. To overcome this, we present a new knowledgebase and the online tool, Gene Ontology Analysis by the Integrated Data Science Laboratory for Metabolomics and Exposomics (IDSL.GOA) to conduct GO over-representation analysis for a metabolite list. The IDSL.GOA knowledgebase covers 2,324 metabolic GO terms and associated 2,818 genes, 22,264 transcripts, 20,158 proteins, 1,482 EC annotations, 2,430 reactions and 2,212 metabolites. IDSL.GOA analysis of a case study of older vs young female brain cortex metabolome highlighted over 250 GO terms being significantly overrepresented (FDR <0.05). The analysis suggested that in the older female brain cortex region, nucleotide salvage processes are severely affected. On contrast, for the same metabolite list, MetaboAnalyst and Reactome Pathway Analysis suggested less than 5 pathways at FDR <0.05, and none of them were related to nucleotide salvage pathways. We showed how IDSL.GOA identified key and relevant GO metabolic processes that were not mentioned by alternative pathway analysis approaches. Overall, we suggest that metabolomics researchers should not limit the interpretation of metabolite lists to only pathway maps and can also leverage GO terms as well. IDSL.GOA provides a powerful tool for this purpose, allowing for a more comprehensive and accurate analysis of metabolite pathway data. IDSL.GOA tool can be accessed at https://goa.idsl.me/.