{"title":"Relationship between inflammation/immunity and epilepsy: A multi-omics mendelian randomization study integrating GWAS, eQTL, and mQTL data","authors":"Jing Mu, Changqing Cao, Yigu Gong, Guiying Hu","doi":"10.1016/j.yebeh.2024.110112","DOIUrl":null,"url":null,"abstract":"<div><h3>Objectives</h3><div>Increasing evidence suggests that activated innate/adaptive immunity induces an inflammatory response, thereby participating in epileptogenesis. However, the biological explanation of inflammation/immunity as a potential cause for epilepsy remains largely unknown. This research aimed to determine the causal effects of inflammation/immune-related genes in epilepsy based on multi-omics mendelian randomization (MR).</div></div><div><h3>Methods</h3><div>We employed summary-data-based MR (SMR) approach to combine GWAS for epilepsy (12,891 cases and 312,803 control) with gene expression quantitative trait loci (<em>cis</em>-eQTL, 31,684 participants) and DNA methylation QTL (<em>cis</em>-mQTL, 1,980 participants) data. Five additional MR methods were then used for sensitivity analyses to confirm the reliability of causal associations. In addition, enrichment analysis of key genes was conducted to provide insight into the biological functions of epilepsy risk variants.</div></div><div><h3>Results</h3><div>A total of 386 inflammation/immune-related genes were selected for further analyses. Primary SMR analysis indicated that 37 DNA methylation sites and six genes regulated by them had potential causal relationship with epilepsy. MR analysis further refined the results, identifying three genes that had a causal effect on epilepsy. Notably, VEGFA (OR: 0.925; 95 % CI: 0.862–0.994) expression was negatively correlated with epilepsy risk, whereas IL16 (OR: 1.076; 95 % CI: 1.028–1.126) and HLA-DPA1 (OR: 1.041; 95 % CI: 1.009–1.074) expressions were positively associated with epilepsy risk. Functional enrichment analysis revealed that the identified genes were involved in GO-BP terms related to VEGF activation signaling and chemotaxis regulation.</div></div><div><h3>Conclusion</h3><div>This analysis confirms the causal role of inflammation/immunity in epilepsy, and the identified candidate genes provide clues for drug development in clinical practice.</div></div>","PeriodicalId":11847,"journal":{"name":"Epilepsy & Behavior","volume":"161 ","pages":"Article 110112"},"PeriodicalIF":2.3000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Epilepsy & Behavior","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1525505024004943","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Objectives
Increasing evidence suggests that activated innate/adaptive immunity induces an inflammatory response, thereby participating in epileptogenesis. However, the biological explanation of inflammation/immunity as a potential cause for epilepsy remains largely unknown. This research aimed to determine the causal effects of inflammation/immune-related genes in epilepsy based on multi-omics mendelian randomization (MR).
Methods
We employed summary-data-based MR (SMR) approach to combine GWAS for epilepsy (12,891 cases and 312,803 control) with gene expression quantitative trait loci (cis-eQTL, 31,684 participants) and DNA methylation QTL (cis-mQTL, 1,980 participants) data. Five additional MR methods were then used for sensitivity analyses to confirm the reliability of causal associations. In addition, enrichment analysis of key genes was conducted to provide insight into the biological functions of epilepsy risk variants.
Results
A total of 386 inflammation/immune-related genes were selected for further analyses. Primary SMR analysis indicated that 37 DNA methylation sites and six genes regulated by them had potential causal relationship with epilepsy. MR analysis further refined the results, identifying three genes that had a causal effect on epilepsy. Notably, VEGFA (OR: 0.925; 95 % CI: 0.862–0.994) expression was negatively correlated with epilepsy risk, whereas IL16 (OR: 1.076; 95 % CI: 1.028–1.126) and HLA-DPA1 (OR: 1.041; 95 % CI: 1.009–1.074) expressions were positively associated with epilepsy risk. Functional enrichment analysis revealed that the identified genes were involved in GO-BP terms related to VEGF activation signaling and chemotaxis regulation.
Conclusion
This analysis confirms the causal role of inflammation/immunity in epilepsy, and the identified candidate genes provide clues for drug development in clinical practice.
期刊介绍:
Epilepsy & Behavior is the fastest-growing international journal uniquely devoted to the rapid dissemination of the most current information available on the behavioral aspects of seizures and epilepsy.
Epilepsy & Behavior presents original peer-reviewed articles based on laboratory and clinical research. Topics are drawn from a variety of fields, including clinical neurology, neurosurgery, neuropsychiatry, neuropsychology, neurophysiology, neuropharmacology, and neuroimaging.
From September 2012 Epilepsy & Behavior stopped accepting Case Reports for publication in the journal. From this date authors who submit to Epilepsy & Behavior will be offered a transfer or asked to resubmit their Case Reports to its new sister journal, Epilepsy & Behavior Case Reports.