# Smoking and risk of restless leg syndrome: a systematic review, meta-analysis, and Mendelian randomisation

## TL;DR

This study finds that smoking is associated with a higher risk of restless leg syndrome, but genetic analysis suggests no causal link.

## Contribution

The study combines meta-analysis and Mendelian randomisation to explore the causal relationship between smoking and restless leg syndrome.

## Key findings

- Smoking increases the risk of restless leg syndrome (OR = 1.40) according to meta-analysis.
- Pregnant smokers have a significantly higher risk of RLS compared to non-pregnant smokers.
- Mendelian randomisation found no causal association between smoking and RLS (OR = 0.50).

## Abstract

Although the link between smoking and various sleep disorders has been well-established, it is still unknown whether smoking increases the risk of restless legs syndrome (RLS). We investigated this association using a meta-analysis and explored the causality through Mendelian randomisation (MR).

We searched six databases for studies reporting associations between smoking and RLS in overall adults, and the results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). We performed sensitivity, subgroup and meta-regression analyses to identify potential sources of heterogeneity. We obtained data used in MR analyses from the UK Biobank and the Genome-wide Association Studies Catalogue. We applied the inverse-variance weighted method, MR Egger, weighted median, simple mode and weighted mode for data analyses, and further conducted pleiotropy and heterogeneity tests, as well as leave-one-out analyses.

Based on 30 studies, we found that smoking was associated with increased risk of RLS (OR = 1.40; 95% CI = 1.17, 1.67, P < 0.001), with the risk significantly increased (P = 0.04) in pregnant women (OR = 2.41; 95% CI = 1.39, 4.16, P = 0.002) than in the non-pregnant adults (OR = 1.30, 95% CI = 1.09, 1.55, P = 0.004), and in current smokers compared with former smokers (OR = 1.09; 95% CI = 1.02, 1.16, P = 0.01). We identified multi-centre studies, diagnostic criteria for RLS and participants' age as potential sources of heterogeneity; however, MR results did not show any causal association between smoking and RLS (OR = 0.50; 95% CI = 0.16, 1.56, P = 0.23).

Although the meta-analysis suggested that smoking increases the risk of RLS, MR analyses did not provide evidence for a causal relationship. Future studies are needed to elucidate the biological mechanisms underlying this association.

PROSPERO: CRD420251048406.