Identifying therapeutic target genes for migraine by systematic druggable genome-wide Mendelian randomization

Abstract

Background: Currently, the treatment and prevention of migraine remain highly challenging. Mendelian randomization (MR) has been widely used to explore novel therapeutic targets. Therefore, we performed a systematic druggable genome-wide MR to explore the potential therapeutic targets for migraine.

Methods: We obtained data on druggable genes and screened for genes within brain expression quantitative trait locis (eQTLs) and blood eQTLs, which were then subjected to two-sample MR analysis and colocalization analysis with migraine genome-wide association studies data to identify genes highly associated with migraine. In addition, phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic drugs.

Results: We identified 21 druggable genes significantly associated with migraine (BRPF3, CBFB, CDK4, CHD4, DDIT4, EP300, EPHA5, FGFRL1, FXN, HMGCR, HVCN1, KCNK5, MRGPRE, NLGN2, NR1D1, PLXNB1, TGFB1, TGFB3, THRA, TLN1 and TP53), two of which were significant in both blood and brain (HMGCR and TGFB3). The results of phenome-wide research showed that HMGCR was highly correlated with low-density lipoprotein, and TGFB3 was primarily associated with insulin-like growth factor 1 levels.

Conclusions: This study utilized MR and colocalization analysis to identify 21 potential drug targets for migraine, two of which were significant in both blood and brain. These findings provide promising leads for more effective migraine treatments, potentially reducing drug development costs.

Keywords: Druggable target genes; Mendelian randomization; Migraine.

Fig. 1

Overview of this study design. DGIdb: Drug-Gene Interaction Database; eQTL: expression quantitative trait loci; GWAS: genome-wide association studies; PheWAS: Phenome-wide association study; PPI: protein–protein interaction; DSigDB: Drug Signatures Database

Fig. 2

Forest plot of 24 significant genes associated with migraine from blood

Fig. 3

Forest plot of 10 significant genes associated with migraine from brain

Fig. 4

Forest plot of 13 genes associated with commonly used medications for migraine from blood and brain

Fig. 5

GO enrichment results for three terms

Fig. 6

KEGG enrichment results

Fig. 7

PPI network built with STRING

Fig. 8

Molecular docking results of available proteins and drugs. a TGFB1 docking butyric acid, b TGFB1 docking clofibrate, c TGFB1 docking Sorafenib, d TGFB1 docking Andrographolide, e TGFB3 docking butyric acid, f EP300 docking butyric acid, g TP53 docking butyric acid, h CDK4 docking clofibrate, i CDK4 docking Sorafenib, j CDK4 docking Andrographolide, k HMGCR docking clofibrate, l TP53 docking clofibrate, m TP53 docking Sorafenib, n TP53 docking Andrographolide