Integrating Pharmacodynamic Data to Prioritise Candidate Migraine Genes and Pathways Using a Novel Bioinformatics...

Background/Objectives: Migraine is a neurological disorder with a heterogeneous presentation; however, compounds perceived as effective by migraine sufferers are often underrepresented in research. This study adopts a novel exploratory approach to determine whether pharmacodynamic data from such compounds can be used to prioritise candidate migraine-related genes and biological pathways for future investigation, and to generate hypotheses regarding migraine pathophysiology. Methods: A structured internet search identified 181 compounds perceived as effective for migraine, of which 148 had at least one supportive report identified in the PubMed literature. Following DrugBank-based exclusions for insufficient interaction data, 137 compounds remained for analysis. A gene list was extrapolated from compound-protein interactions, followed by analyses identifying significantly enriched tissues and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. Unique genes from enriched tissue-specific sublists were considered targets of interest, and those not previously directly associated with migraine in the databases and literature searches used were deemed candidate migraine target genes. Results: A total of 32 compounds affected the products of 21 targets of interest. CHRM3, CHRNA4, and SCN2B emerged as prioritised candidate genes that had not previously been directly associated with migraine in the databases examined. Enrichment analysis of the pharmacodynamically derived gene set identified tissue-enrichment signals involving skeletal muscle (q = 6.01 × 10^-5), prefrontal cortex (q = 5.36 × 10^-3), cerebellar peduncles (q = 1.28 × 10^-2) and cerebellum (q = 4.79 × 10^-2). Nine compounds interacting with established Familial Hemiplegic Migraine (FHM) genes may warrant future investigation. No conclusions regarding therapeutic efficacy are drawn from these data. Conclusions: This exploratory pipeline prioritised CHRM3, CHRNA4, and SCN2B as candidate genes for further investigation, alongside enriched tissues and pathways. These findings should be regarded as hypothesis-generating rather than evidence of causality or therapeutic utility. More broadly, variations of this prioritisation framework may prove useful for exploring other disorders.