Proteome-wide Mendelian randomization identified potential drug targets for migraine

Abstract

Background: Migraine is a highly prevalent and complex neurovascular disease. However, the currently available therapeutic drugs often fall to adequately meet clinical needs due to limited effectiveness and numerous undesirable side effects. This study aims to identify putative novel targets for migraine treatment through proteome-wide Mendelian randomization (MR).

Methods: We utilized MR to estimate the causal effects of plasma proteins on migraine and its two subtypes, migraine with aura (MA) and without aura (MO). This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association studies (GWAS) findings for these migraine phenotypes. Moreover, we conducted a phenome-wide MR assessment, enrichment analysis, protein-protein interaction networks construction, and mediation MR analysis to further validate the pharmaceutical potential of the identified protein targets.

Results: We identified 35 protein targets for migraine and its subtypes (p < 8.04 × 10^-6), with prioritized targets showing minimal side effects. Phenome-wide MR identified novel protein targets-FCAR, UBE2L6, LATS1, PDCD1LG2, and MMP3-that have no major disease side effects and interacted with current acute migraine medication targets. Additionally, MMP3, PDCD1LG2, and HBQ1 interacted with current preventive migraine medication targets. The causal effects of plasma protein on migraine were partly mediated by plasma metabolites (proportion of mediation from 3.8% to 21.0%).

Conclusions: A set of potential protein targets for migraine and its subtypes were identified. These proteins showed rare side effects and were responsible for biological mechanisms involved in migraine pathogenesis, indicating priority for the development of migraine treatments.

Keywords: Drug targets; Mendelian randomization; Migraine; Proteomics.

Fig. 1

Study design for identification of plasma proteins causally associated with migraine

Fig. 2

MR results for plasma proteins and the risk of migraine, MO and MA. The forest plot of the MR results for 2073 plasma proteins on the risk of migraine (A), MO (B) and MA (C). Each box represents the effect (i.e., OR change) per 1 SD change in the respective plasma proteins on migraine (A), MO (B) and MA (C), respectively and the error bars represent 95% CI. Arrows indicate that 95% CI exceeds the x axis. Bonfferoni corrected P = 8.04E-06 (0.05/2073/3). Abbreviations: OR, odds ratio; CI, confidence interval

Fig. 3

Major expression regions and cortical metabolism patterns of target genes. A Brain plots of 12 major expression regions of migraine-related genes. Overview of linear regression results between migraine-related genes expression profile and five cortical metabolism properties included in GAMBA. Dark blue indicates significant (Bonferroni p < 0.05). B Brain plots of 12 major expression regions of MO-related genes. Overview of linear regression results between migraine-related genes expression profile and five cortical metabolism properties included in GAMBA. Dark blue indicates significant (Bonferroni p < 0.05). C Brain plots of 12 major expression regions of MA-related genes. Overview of linear regression results between migraine-related genes expression profile and five cortical metabolism properties included in GAMBA. Dark blue indicates significant (Bonferroni p < 0.05). Abbreviations: GI, glycolytic index; OGI, oxygen-glucose index, CMRO2, cerebral metabolic rate for oxygen; CMRGlu, cerebral metabolic rate for glucose; CBF, cerebral blood flow

Fig. 4

Interaction between commonly used acute and preventive migraine medications targets and identified potential drug targets. The migraine-associated proteins, including LATS1, FCAR, MMP3, and UBE2L6, as well as MO-association proteins PDCD1LG2 and MA-related proteins MMP3, were linked to acute migraine drugs. The common protein MMP3 for migraine and MA, as well as the MO-related protein HBQ1, are associated with preventive migraine drugs

Fig. 5

Mediation effects of protein on migraine via plasma metabolites. Mediation analyses to quantify the effects of proteins with PPI on migraine, MO and MA outcomes via plasma metabolites. A MMP3 effect on migraine mediated by 21-hydroxypregnenolone disulfate. B MMP3 effect on migraine mediated by Glucuronate/Androsterone glucuronide; (C) PDCD1LG2 effect on MO mediated by Gamma-glutamylglutamine; (D) PDCD1LG2 effect on MO mediated by partially characterized molecules; (E) PDCD1LG2 effect on MO mediated by 3-hydroxysebacate; (F) MMP3 effect on MA mediated by sphingomyelin. β_EM, effects of exposure on mediator, β_MO, effects of mediator on outcome, β_EO, effects of exposure on outcome