Precision Target Discovery for Migraine: An Integrated GWAS-eQTL-PheWAS Pipeline
Abstract
1. Introduction
2. Results
2.1. SMR Main Analysis
2.2. Identification and Profiles of Screened Druggable Genes
2.3. MR Analysis Results Based on Multiple Methods
2.4. Colocalization Analysis of Druggable Genes
2.5. Exploration of the Druggability Potential of Genes
2.6. Enrichment Analysis
2.7. PheWAS Analysis
2.8. Potential Targeted Drug Prediction
3. Discussion
3.1. Causal Associations and Biological Mechanisms
3.2. Translational Implications: Drug Targets and Repurposing
3.3. Cross-Study Comparison and Verification
3.4. Limitations and Future Research Directions
- (1)
- Conduct cross-ancestry validation studies to explore the impact of gene-environment interaction on migraine;
- (2)
- Verify the functions of key genes (such as MICU1, UFL1, LY6G5C, PPP1CC) in the pathology of migraine through CRISPR/Cas9 or animal models;
- (3)
- Develop targeted regulatory strategies for genes such as NR1D1, THRA, NCOR2, CHD4, and evaluate their roles in neuroinflammation and synaptic plasticity;
- (4)
- Design multi-target combination therapies tailored to the different phases of migraine (e.g., acute vs. preventive), and integrate real-world adverse reaction data from monotherapies [55] to optimize treatment safety and efficacy.
4. Materials and Methods
4.1. Study Design
4.2. Screening of Genetic Tools for Target Gene Expression
4.3. Migraine GWAS Data
4.4. Data Analysis
4.5. Sensitivity Analysis of Key Target Genes
4.6. External Validation Analysis
4.7. Screening of Druggable Genes
4.8. Candidate Gene Selection and Functional Enrichment Analysis
4.9. PheWAS Analysis of Candidate Gene
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
GWASs | Genome-wide association studies |
eQTL | Expression quantitative trait loci |
MR | Mendelian randomization |
IV (IVs) | Instrumental variable (s) |
SMR | Summary-based Mendelian randomization |
HEIDI | Heterogeneity in dependent instruments |
SNP(s) | Single nucleotide polymorphism(s) |
PPI | Protein–protein interaction |
PheWASs | Phenome-wide association studies |
GO enrichment | Gene Ontology enrichment |
LD | Linkage disequilibrium |
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Source | Tissue | Gene |
---|---|---|
eQTLGen | Whole Blood | TJP2, B9D2, CCDC97, SNORA63, THRA, NR1D1, LY6G5C, RNFT2, PABPC4, ZC3H6, HRK, PPP1CC, SHISA5, UBE2D3-AS1, DNAJB12, RALGAPA1, CISD2, FAM8A1, PRR13, SFXN2, NCOR2, KLF10, GBA2, RGP1, PAM16, TGFB3, HVCN1, CHD4, ZMYND12, CCDC18-AS1, AURKC, RCCD1, RPS16 (novel transcript), RP11-252K23.2 (novel transcript), CTC-444N24.8 (novel transcript) |
PsychENCODE | Prefrontal Cortex | KIAA0040, CFDP1, SLC9B1, CARF, ID4, CISD2, HMGXB3, RABAC1, RIMS1, UBE2D3-AS1, POLR1B, INPP5B, TREX1, TMA7, IPO8, SHISA5, EAPP, PACSIN3, SNX6, BICD1, RALGAPA1, CCDC18-AS1, ZMYND12 |
GTEx V8 | Cerebellar Hemisphere | UFL1, LY6G5C, POC5, RCCD1, EXOSC5 |
Cerebellum | UFL1, LY6G5C, RP11-753C18.8 | |
Whole Blood | UFL1, LY6G5C, FBXW8, LY6G5B, CTD-2509G16.2, RALGAPA1, PABPC4, HRK, ATP5SL |
Tissue | Gene | Source | Chr | Top SNP | b_SMR | se_SMR | p_SMR | p_HEIDI | nsnp_HEIDI | FDR |
---|---|---|---|---|---|---|---|---|---|---|
Blood | AURKC | eQTLGen | 19 | rs2074858 | −0.309 | 0.082 | 1.68 × 10−4 | 0.277 | 20 | 0.049 |
Blood | CHD4 | eQTLGen | 12 | rs7969177 | 0.281 | 0.073 | 1.17 × 10−4 | 0.149 | 20 | 0.037 |
Blood | GBA2 | eQTLGen | 9 | rs10814274 | −0.068 | 0.017 | 7.54 × 10−5 | 0.173 | 20 | 0.030 |
Blood | HVCN1 | eQTLGen | 12 | rs113511140 | 0.168 | 0.044 | 1.17 × 10−4 | 0.306 | 20 | 0.037 |
Blood | NCOR2 | eQTLGen | 12 | rs1271309 | −0.312 | 0.078 | 6.86 × 10−5 | 0.312 | 20 | 0.029 |
Blood | NR1D1 | eQTLGen | 17 | rs883871 | 0.177 | 0.038 | 4.05 × 10−6 | 0.556 | 20 | 0.005 |
Blood | TGFB3 | eQTLGen | 14 | rs146047341 | −0.122 | 0.032 | 1.15 × 10−4 | 0.251 | 20 | 0.037 |
Blood | THRA | eQTLGen | 17 | rs883871 | 0.121 | 0.026 | 3.20 × 10−6 | 0.595 | 20 | 0.004 |
Brain—Prefrontal Cortex | BICD1 | PsychENCODE | 12 | rs11051973 | −0.087 | 0.023 | 1.13 × 10−4 | 0.213 | 20 | 0.038 |
Brain—Prefrontal Cortex | IPO8 | PsychENCODE | 12 | rs61923728 | −0.045 | 0.011 | 1.91 × 10−5 | 0.717 | 20 | 0.014 |
Brain—Hippocampus | BACE2 | BrainMeta v1 | 21 | rs914187 | 0.051 | 0.013 | 7.08 × 10−5 | 0.887 | 20 | 0.013 |
Brain—Cerebellum | CHRNB1 | BrainMeta v1 | 17 | rs60488855 | −0.101 | 0.026 | 8.94 × 10−5 | 0.053 | 20 | 0.042 |
Brain—Cerebellum | REV3L | BrainMeta v2 | 6 | rs12214097 | 0.052 | 0.015 | 3.53 × 10−4 | 0.683 | 20 | 0.046 |
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Liu, X.; Liu, Q.; Zhu, H.; Zhou, X.; Li, X.; Hu, M.; Peng, F.; Ji, J.; Yang, S. Precision Target Discovery for Migraine: An Integrated GWAS-eQTL-PheWAS Pipeline. Molecules 2025, 30, 3921. https://doi.org/10.3390/molecules30193921
Liu X, Liu Q, Zhu H, Zhou X, Li X, Hu M, Peng F, Ji J, Yang S. Precision Target Discovery for Migraine: An Integrated GWAS-eQTL-PheWAS Pipeline. Molecules. 2025; 30(19):3921. https://doi.org/10.3390/molecules30193921
Chicago/Turabian StyleLiu, Xianting, Qingming Liu, Haoning Zhu, Xiao Zhou, Xinyao Li, Ming Hu, Fu Peng, Jianguang Ji, and Shu Yang. 2025. "Precision Target Discovery for Migraine: An Integrated GWAS-eQTL-PheWAS Pipeline" Molecules 30, no. 19: 3921. https://doi.org/10.3390/molecules30193921
APA StyleLiu, X., Liu, Q., Zhu, H., Zhou, X., Li, X., Hu, M., Peng, F., Ji, J., & Yang, S. (2025). Precision Target Discovery for Migraine: An Integrated GWAS-eQTL-PheWAS Pipeline. Molecules, 30(19), 3921. https://doi.org/10.3390/molecules30193921