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...
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BMC
2024-11-01
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| Series: | The Journal of Headache and Pain |
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| Online Access: | https://doi.org/10.1186/s10194-024-01922-z |
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| author | Jiafei Lou Miaoqian Tu Maosheng Xu Zhijian Cao Wenwen Song |
| author_facet | Jiafei Lou Miaoqian Tu Maosheng Xu Zhijian Cao Wenwen Song |
| author_sort | Jiafei Lou |
| collection | DOAJ |
| description | 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 composition traits, suggesting drug safety considerations. Conclusion PNKP and MRVI1 exhibit dual mechanisms of action at the gene and protein levels, potentially involving distinct mechanistic pathways. Among them, PNKP emerges as a promising drug target for migraine treatment, supported by multi-layered validation. |
| format | Article |
| id | doaj-art-afdbff69a3704a6ea9abb9f0c586134c |
| institution | OA Journals |
| issn | 1129-2377 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | The Journal of Headache and Pain |
| spelling | doaj-art-afdbff69a3704a6ea9abb9f0c586134c2025-08-20T02:33:00ZengBMCThe Journal of Headache and Pain1129-23772024-11-0125111510.1186/s10194-024-01922-zPlasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiologyJiafei Lou0Miaoqian Tu1Maosheng Xu2Zhijian Cao3Wenwen Song4Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)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 composition traits, suggesting drug safety considerations. Conclusion PNKP and MRVI1 exhibit dual mechanisms of action at the gene and protein levels, potentially involving distinct mechanistic pathways. Among them, PNKP emerges as a promising drug target for migraine treatment, supported by multi-layered validation.https://doi.org/10.1186/s10194-024-01922-zMigraineMendelian randomizationGene regulationProtein expressionMetabolic pathwaysDrug development |
| spellingShingle | Jiafei Lou Miaoqian Tu Maosheng Xu Zhijian Cao Wenwen Song Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology The Journal of Headache and Pain Migraine Mendelian randomization Gene regulation Protein expression Metabolic pathways Drug development |
| title | Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology |
| title_full | Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology |
| title_fullStr | Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology |
| title_full_unstemmed | Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology |
| title_short | Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology |
| title_sort | plasma pqtl and brain eqtl integration identifies pnkp as a therapeutic target and reveals mechanistic insights into migraine pathophysiology |
| topic | Migraine Mendelian randomization Gene regulation Protein expression Metabolic pathways Drug development |
| url | https://doi.org/10.1186/s10194-024-01922-z |
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