Decoding migraine disorders: parathyroid hormone-related peptide receptors as key genetic drivers

Migraine is a complex neurological disorder, and the most common migraine categories are migraine with aura and without aura. The higher prevalence of migraine in related individuals compared to the general population indicates a potential genetic predisposition; however, gene expression, which is influenced by both genetic and environmental factors, can also be a major factor in the migraine susceptibility. Given the high number of Portuguese migraine patients whose diagnosis and treatment have not yet been well established, we decided to carry out a whole transcriptome analysis within a migraine Portuguese cohort. This study aims to identify potential biomarkers that could contribute to improved migraine therapy. We performed total RNA sequencing on whole blood samples from 15 migraine patients and 12 age-matched controls. Differential expression analysis and gene set enrichment analysis were performed in different migraine subgroups. Finally, we performed the protein-protein interaction networks of differentially expressed genes. Gene set enrichment analysis comparing migraine patients with controls highlighted upregulated pathways linked to metabolism, and downregulated immuno-inflammatory pathways. Moreover, the groups of female migraine patients and female migraine without aura patients emphasized significant upregulated pathways, including G protein-coupled receptors signalling pathways, when compared with female controls. Interestingly, we found two important differentially expressed genes related to parathyroid hormone: PTH1R and PTH2. PTH1R was upregulated in female migraine without aura versus female controls, while PTH2 was both upregulated between female migraine patients and female controls, as well as between female migraine without aura and controls. Here, we show, for the first time, the involvement of parathyroid hormone receptors and their associated gene expression patterns in female migraine patients. These molecules stand out as sturdy and promising biomarkers for innovative therapeutic in female migraine patients.