# Exploring Contraindicated Medications and Corresponding Targeted Genes for Migraine Through Integrated Genetic Approaches

## TL;DR

This study identifies medications that may worsen migraine and its subtypes and finds specific genes linked to these drugs, offering new insights for prevention.

## Contribution

The study integrates genetic and drug data to identify contraindicated medications and their target genes for migraine and its subtypes.

## Key findings

- Diuretics and renin-angiotensin system agents are linked to increased migraine risk.
- 37 and 22 target genes were identified for migraine and migraine with aura, respectively.
- Genes like SERPINC1 and PAM showed significant associations across multiple brain regions.

## Abstract

To identify contraindicated medications and corresponding target genes for migraine and its subtypes.

Utilizing the Genome‐Wide Association Studies (GWAS) for 14 medication‐use categories from UK Biobank and GWAS for migraine and its subtypes from FinnGen, our study revealed potential contraindicated drugs for the chronic paroxysmal neurological disorder based on Mendelian randomization (MR). Then we applied the Transcriptome‐wide association study (TWAS) within the framework of Omnibus Transcriptome Test using Expression Reference Summary data (OTTERS) and cross‐referenced three drug databases to determine the targeted genes of the identified contraindicated medications. Moreover, Summary‐data‐based Mendelian Randomization (SMR) and INtegration of TWAS And ColocalizaTion (INTACT) were used as sensitivity analyses to further validate the associations and strengthen causal inference. We also performed brain‐tissue TWAS across 13 regions to confirm the tissue‐specific associations of the hub genes with migraine and its subtypes.

MR analysis revealed that the diuretics and agents that act on the renin‐angiotensin system were discovered to be associated with an increased risk of migraine and migraine with aura. By intersecting the results from TWAS and drug databases, 37 and 22 target genes of contraindicated medications were identified for migraine and migraine with aura, respectively. SMR and INTACT confirmed the validity of BLM, C12orf76, GPATCH4, PAM, SERPINC1 for migraine, and ALMS1, GPATCH4, NCF2, SLC12A1, ZKSCAN8P1 for migraine with aura. At the brain‐tissue level, we further validated hub gene associations: in migraine, SERPINC1, ZKSCAN8P1, C12orf76, and PAM were significant across brain regions; in migraine with aura, SERPINC1, ALMS1, ZKSCAN8P1, PAM, and NCF2 were significant.

We identified the diuretics and agents that act on the renin‐angiotensin system as the contraindicated medications for migraine and migraine with aura, and BLM, C12orf76, GPATCH4, PAM, SERPINC were found as the targeted genes of contraindicated drugs for migraine and ALMS1, GPATCH4, NCF2, SLC12A1, ZKSCAN8P1 for migraine with aura, providing new clues for the preventive strategies for migraine and its subtypes.

To systematically identify risk medications for migraine and its subtypes, we integrated GWAS data for 23 medications with GWASs of migraine and its subtypes to conduct causal inference. We then combined plasma eQTLs with drug‐target databases to map putative targets of the risk medications and validated causal relationships using colocalization and SMR analyses. In total, we identified six drug‐target genes associated with migraine risk and six associated with migraine with aura, with their associations replicated across 13 brain regions.