Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine

Abstract

Introduction: Migraine, as a complex neurological disease, brings heavy burden to patients and society. Despite the availability of established therapies, existing medications have limited efficacy. Thus, we aimed to find the drug targets that improve the prognosis of migraine.

Method: We used Mendelian Randomization (MR) and Summary-data-based MR (SMR) analyses to study possible drug targets of migraine by summary statistics from FinnGen cohorts (nCase = 44,616, nControl = 367,565), with further replication in UK Biobank (nCase = 26,052, nControl = 487,214). Genetic instruments were obtained from eQTLGen and UKB-PPP to verify the drug targets at the gene expression and protein levels. The additional analyses including Bayesian co-localization, the heterogeneity in dependent instruments(HEIDI), Linkage Disequilibrium Score(LDSC), bidirectional MR, multivariate MR(MVMR), heterogeneity test, horizontal pleiotropy test, and Steiger filtering were implemented to consolidate the findings further. Lastly, drug prediction analysis and phenome-wide association study(PheWAS) were employed to imply the possibility of drug targets for future clinical applications.

Result: The MR analysis of eQTL data showed that four drug targets (PROCR, GSTM4, SLC4A1, and TNFRSF10A) were significantly associated with migraine risk in both the FinnGen and UK Biobank cohorts. However, only GSTM4 exhibited consistent effect directions across the two outcomes(Discovery cohort: OR(95%CI) = 0.94(0.93-0.96); p = 2.70e - 10; Replication cohort: OR(95%CI) = 0.93(0.91-0.94); p = 4.21e - 17). Furthermore, GSTM4 passed the SMR at p < 0.05 and HEIDI test at p > 0.05 at both the gene expression and protein levels. The protein-level MR analysis revealed a strong correlation between genetically predicted GSTM4 with a lower incidence of migraine and its subtypes(Overall migraine: OR(95%CI) = 0.91(0.87-0.95); p = 6.98e-05; Migraine with aura(MA): OR(95%CI) = 0.90(0.85-0.96); p = 2.54e-03; Migraine without aura(MO): OR(95%CI) = 0.90(0.83-0.96); p = 2.87e-03), indicating a strong co-localization relationship (PPH4 = 0.86). Further analyses provided additional validation for the possibility of GSTM4 as a migraine treatment target.

Conclusion: This study identifies GSTM4 as a potential druggable gene and promising therapeutic target for migraine.

Keywords: Colocalization analyses; Drug target; GSTM4; Mendelian randomization; Migraine; Summary-data-based MR.

Fig. 1

Overview of the study design

Fig. 2

Venn diagram of three datasets

Fig. 3

Manhattan plot for correlation of druggable genes with migraine in MR analysis

Fig. 4

Forest plots illustrating the results of the discovery stage for 14 essential genes

Fig. 5

Forest plots illustrating the results of the replication stage for 12 genes

Fig. 6

The SMR locus plots and effects plots for correlations of GSTM4 in gene expression with migraine

Fig. 7

Forest plots illustrating the results of circulating GSTM4 and subgroup analysis

Fig. 8

Regional plot of colocalization evidence of GSTM4 and migraine

Fig. 9

The SMR locus plots and effects plots for correlations of circulating GSTM4 with migraine

Fig. 10

Associations between GSTM4 and migraine risk factors

Fig. 11

The expression of GSTM4 in human tissues and brain regions

Fig. 12

Binary traits PheWAS association with GSTM4