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      Role of inflammatory cytokine in mediating the effect of plasma lipidome on epilepsy: a mediation Mendelian randomization study

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          Abstract

          Background

          Epilepsy is one of the most prevalent serious brain disorders globally, impacting over 70 million individuals. Observational studies have increasingly recognized the impact of plasma lipidome on epilepsy. However, establishing a direct causal link between plasma lipidome and epilepsy remains elusive due to inherent confounders and the complexities of reverse causality. This study aims to investigate the causal relationship between specific plasma lipidome and epilepsy, along with their intermediary mediators.

          Methods

          We conducted a two-sample Mendelian randomization (MR) and mediation MR analysis to evaluate the causal effects of 179 plasma lipidomes and epilepsy, with a focus on the inflammatory cytokine as a potential mediator based on the genome-wide association study. The primary methodological approach utilized inverse variance weighting, complemented by a range of other estimators. A set of sensitivity analyses, including Cochran’s Q test, I 2 statistics, MR-Egger intercept test, MR-PRESSO global test and leave-one-out sensitivity analyses was performed to assess the robustness, heterogeneity and horizontal pleiotropy of results.

          Results

          Our findings revealed a positive correlation between Phosphatidylcholine (18:1_18:1) levels with epilepsy risk (OR = 1.105, 95% CI: 1.036–1.178, p = 0.002). Notably, our mediation MR results propose Tumor necrosis factor ligand superfamily member 12 levels (TNFSF12) as a mediator of the relationship between Phosphatidylcholine (18,1_18:1) levels and epilepsy risk, explaining a mediation proportion of 4.58% [mediation effect: ( b = 0.00455, 95% CI: −0.00120-0.01030), Z = 1.552].

          Conclusion

          Our research confirms a genetic causal relationship between Phosphatidylcholine (18:1_18:1) levels and epilepsy, emphasizing the potential mediating role of TNFSF12 and provide valuable insights for future clinical investigations into epilepsy.

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          Most cited references48

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          Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases

          Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the ‘no horizontal pleiotropy’ assumption can cause severe bias in MR. We developed the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that MR-PRESSO is best suited when horizontal pleiotropy occurs in <50% of instruments. Next, we applied MR-PRESSO, along with several other MR tests to complex traits and diseases, and found that horizontal pleiotropy: (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from −131% to 201%; (iii) induced false positive causal relationships in up to 10% of relationships; and (iv) can be corrected in some but not all instances.
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            Interpreting findings from Mendelian randomization using the MR-Egger method

            Mendelian randomization-Egger (MR-Egger) is an analysis method for Mendelian randomization using summarized genetic data. MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2) a test for a causal effect, and (3) an estimate of the causal effect. While conventional analysis methods for Mendelian randomization assume that all genetic variants satisfy the instrumental variable assumptions, the MR-Egger method is able to assess whether genetic variants have pleiotropic effects on the outcome that differ on average from zero (directional pleiotropy), as well as to provide a consistent estimate of the causal effect, under a weaker assumption—the InSIDE (INstrument Strength Independent of Direct Effect) assumption. In this paper, we provide a critical assessment of the MR-Egger method with regard to its implementation and interpretation. While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. The issues raised in this paper have potentially serious consequences for causal inferences from the MR-Egger approach. We give examples of scenarios in which the estimates from conventional Mendelian randomization methods and MR-Egger differ, and discuss how to interpret findings in such cases. Electronic supplementary material The online version of this article (doi:10.1007/s10654-017-0255-x) contains supplementary material, which is available to authorized users.
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              Mendelian randomization: genetic anchors for causal inference in epidemiological studies

              Observational epidemiological studies are prone to confounding, reverse causation and various biases and have generated findings that have proved to be unreliable indicators of the causal effects of modifiable exposures on disease outcomes. Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits. The approach is being widely applied, and various ways to strengthen inference given the known potential limitations of MR are now available. Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review. The integration of genetic information into population-based epidemiological studies presents translational opportunities, which capitalize on the investment in genomic discovery research.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2623287/overviewRole: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Role: Role: Role: Role: Role:
                Role: Role: Role:
                Role: Role: Role:
                Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2532298/overviewRole: Role: Role:
                URI : https://loop.frontiersin.org/people/2421970/overviewRole: Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1812659/overviewRole: Role: Role: Role: Role:
                Role: Role: Role: Role: Role:
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                30 May 2024
                2024
                : 15
                : 1388920
                Affiliations
                [1] 1Department of Neurology, Fujian Medical University Union Hospital , Fuzhou, China
                [2] 2Fujian Key Laboratory of Molecular Neurology , Fuzhou, China
                [3] 3Department of Geriatrics, Fujian Medical University Union Hospital , Fuzhou, China
                Author notes

                Edited by: Andrea Romigi, Università Telematica Internazionale Uninettuno, Italy

                Reviewed by: Youjie Zeng, Central South University, China

                Xiaoyan Hao, First Affiliated Hospital of Zhengzhou University, China

                *Correspondence: Wanhui Lin, wanhuilin@ 123456fjmu.edu.cn ; Shenggen Chen, shenggenchen@ 123456fjmu.edu.cn ; Huapin Huang, 9198615016@ 123456fjmu.edu

                These authors have contributed equally to this work and share first authorship

                Article
                10.3389/fneur.2024.1388920
                11169836
                38872823
                03d8f61b-22c2-4716-a089-6e08d63cffc7
                Copyright © 2024 Wang, Xiong, Li, Wu, Zhang, Zhu, Lin, Chen and Huang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 February 2024
                : 13 May 2024
                Page count
                Figures: 4, Tables: 3, Equations: 0, References: 48, Pages: 9, Words: 5336
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was financially supported by a research fund from the Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital (2022XH037), National key clinical specialty (Grant No. 21281003), Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province(2022Y2005) and Provincial Clinical Key Specialty Construction Project(2128200737).
                Categories
                Neurology
                Original Research
                Custom metadata
                Epilepsy

                Neurology
                epilepsy,phosphatidylcholine (18:1_18:1),tnfsf12,causal relationship,mr analysis,mediation mr analysis

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