# The causal relationship between systemic lupus erythematosus and juvenile myoclonic epilepsy: A Mendelian randomization study and mediation analysis

## TL;DR

This study finds a genetic link between systemic lupus erythematosus and juvenile myoclonic epilepsy, but no clear mediators were identified.

## Contribution

The study provides new evidence of a causal genetic relationship between SLE and JME using Mendelian randomization.

## Key findings

- Genetic susceptibility to SLE is causally linked to an increased risk of JME.
- Inflammatory cytokines were not identified as mediators between SLE and JME.
- Other systemic autoimmune disorders were not found to be causally associated with JME.

## Abstract

This study aimed to investigate the causal relationship between systemic lupus erythematosus (SLE) and juvenile myoclonic epilepsy (JME). Univariable and reverse Mendelian randomization (MR) analyses were performed to investigate the potential causal associations between SLE, systemic autoimmune disorders (SADs), and JME. Two‐step mediation MR analysis was further performed to explore indirect factors that may influence the relationship between SLE and JME. Summary data on SADs were extracted from the Integrative Epidemiology Unit Open genome‐wide association study database, and summary statistics for JME were acquired from the International League Against Epilepsy Consortium. The inverse‐variance weighted (IVW) method was used for primary analysis, supplemented by MR‐Egger and weighted median. In the univariable MR analysis, IVW results indicated a causal relationship between SLE and an increased risk of JME (odds ratio = 1.0030, 95% confidence interval, 1.0004–1.0057; p = 0.023). The subsequent mediation MR analysis showed that inflammatory cytokines may not be the mediating factors between SLE and JME, while the inverse MR analysis found no significant relationship. Our study indicated that genetic susceptibility to SLE was causally linked to JME. However, subsequent mediation analysis failed to identify the potential mediators that could influence this relationship. Moreover, evidence suggested that other SADs were not causally associated with JME. This study may provide guidance for screening risk factors for seizures and exploring potential treatments in SLE and JME, and even all SADs and JME.

Mendelian randomization (MR) studies were conducted using the inverse‐variance weighted (IVW) method, MR‐Egger and weighted median on juvenile myoclonic epilepsy (JME), and systemic lupus erythematosus (SLE) data from the Integrative Epidemiology Unit (IEU) Open genome‐wide association study (GWAS) database and the International League Against Epilepsy (ILAE) Consortium. Research suggested a causal relationship between the genetic susceptibility of SLE and JME, and there was almost no evidence in reverse MR analysis to suggest a causal genetic relationship between JME and SLE. There may be a potential connection between SLE and JME, in which antineuronal antibodies, inflammatory cytokines, or genetic factors may play an important role. There was no relationship between other systemic autoimmune diseases and JME. Other evidence suggested that inflammatory cytokines were not causally linked to JME. This study may provide guidance for screening risk factors for seizures and exploring potential treatments in SLE and JME, and even all systemic autoimmune disorders and JME.