Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology
Abstract
BACKGROUND: Migraine is a prevalent neurological disorder affecting 14.1% of the global population. Despite advances in genetic research, further investigation is needed to identify therapeutic targets and better understand its mechanisms. In this study, we aimed to identify drug targets and explore the relationships between gene expression, protein levels, and migraine pathophysiology.
METHODS: We utilized cis-pQTL data from deCODE Genetics, combined with migraine GWAS data from the GERA + UKB cohort as the discovery cohort and the FinnGen R10 cohort as the replication cohort. SMR and MR analyses identified migraine-associated protein loci. Brain eQTL data from GTEx v8 and BrainMeta v2 were used to explore causal relationships between gene expression, protein levels, and migraine risk. Mediation analysis assessed the role of metabolites, and PheWAS evaluated potential side effects.
RESULTS: Four loci were identified: PNKP, MRVI1, CALCB, and INPP5B. PNKP and MRVI1 showed a high level of evidence and opposing effects at the gene and protein levels. PNKP gene expression in certain brain regions was protective against migraine, while its plasma protein levels were positively associated with migraine risk. MRVI1 showed protective effects at the protein level but had the opposite effect at the gene expression level. Mediation analysis revealed that the glutamate to pyruvate ratio and 3-CMPFP mediated PNKP's effects on migraine. PheWAS indicated associations between PNKP and body…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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