Causal relationship between rheumatoid arthritis and epilepsy in a European population: a univariate and multivariate Mendelian randomization study

Background Several previous studies have reported an association between rheumatoid arthritis (RA) and epilepsy, but the causal relationship is unclear. The aim of this study was to assess the connection between RA and epilepsy in a European population using Mendelian randomization (MR). Methods Genome-wide association study summary data on RA and epilepsy from European populations were included. Univariate MR (UVMR) and multivariate MR were used to investigate the causal relationship between the two conditions. Three analysis methods were applied: inverse variance weight (IVW), MR-Egger, and weighted median, with IVW being the primary method. Cochran Q statistics, MR-PRESSO, MR-Egger intercept, leave-one-out test, and MR-Steiger test were combined for the sensitivity analysis. Results UVMR showed a positive association between RA and epilepsy risk (OR=1.038, 95% CI=1.007–1.038, p=0.017) that was supported by sensitivity analysis. Further MVMR after harmonizing the three covariates of hypertension, alcohol consumption, and smoking, confirmed the causal relationship between RA and epilepsy (OR=1.049, 95% CI=1.011–1.087, p=0.010). Conclusion This study demonstrated that RA is associated with an increased risk of epilepsy. It has emphasized that the monitoring of epilepsy risk in patients diagnosed with RA should be strengthened in clinical practice, and further studies are needed in the future to explore the potential mechanism of action connecting the two conditions.


Background
Explain the scientific background and rationale for the reported study.What is the exposure?Is a potential causal relationship between exposure and outcome plausible?Justify why MR is a helpful method to address the study question

2-3
Epilepsy is a prevalent and highly disabling chronic central nervous system disorder characterized by sudden abnormal discharges of neurons in the brain resulting in transient dysfunction of the brain.
In recent years, a number of studies have reported an association between RA and epilepsy.
Genetic variants are identified at conception through random assignment, which means that they are not affected by other factors such as behavioral, environmental, and social factors, allowing MR to avoid confounding by confounding factors and reverse causation to the greatest extent possible.
3 Objectives State specific objectives clearly, including pre-specified causal hypotheses (if any).
State that MR is a method that, under specific assumptions, intends to estimate causal effects 3 Mendelian randomization (MR) is an innovative epidemiological approach that uses genetic variants such as single nucleotide diversity (SNPs) as instrumental variables (IVs) to infer potential causal relationships between exposures and outcomes.

Study design and data sources
Present key elements of the study design early in the article.Consider including a table listing sources of data for all phases of the study.For each data source contributing to the analysis, describe the following: a) Setting: Describe the study design and the underlying population, if possible.Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection, when available.

4,Table S1
European population.Considering that the results of UVMR may be affected by potential confounders, we performed further MVMR analysis.After coordinating hypertension, alcohol consumption, and smoking, the IVW method showed that there was still a positive causal association between RA and epilepsy risk.

Data and data sharing
Provide the data used to perform all analyses or report where and how the data can be accessed, and reference these sources in the article.Provide the statistical code needed to reproduce the results in the article, or report whether the code is publicly accessible and if so, where 8 All of the GWAS summary data in our study is available at the GWAS Catalog(https://gwas.mrcieu.ac.uk/).

Table S1 .
b) Participants: Give the eligibility criteria, and the sources and methods of selection of participants.Report the sample size, and whether any power or sample size calculations were carried out prior to the main analysis -statistic was incorporated to ensure that the selected IVs were strong IVs, and usually variables with F-statistic > 10 were defined as strong IVs.c)Describe the MR estimator (e.g.two-stage least squares, Wald ratio) and related statistics.Detail the included covariates and, in case of two-sample MR, whether the same covariate set was used for adjustment in the two samples r2 < 0.001 and distance = 10000 kb for LDclumping to exclude SNPs with strong LD.F

Table S2 Table S2 c
) If the data sources include meta-analyses of previous studies, provide the assessments of heterogeneity across these studies in patients diagnosed with RA as well as individualized assessment should be strengthened in clinical practice, and further studies are needed in the future to explore the potential mechanism of action between the two.17 Generalizability Discuss the generalizability of the study results (a) to other populations, (b) across other exposure periods/timings, and (c) across other levels of exposure 8 the samples included in this study were of European origin and therefore may not be generalizable to other populations OTHER INFORMATION 18 Funding Describe sources of funding and the role of funders in the present study and, if applicable, sources of funding for the databases and original study or studies on which the present study is based