Association among attention-deficit hyperactivity disorder, restless legs syndrome, and peripheral iron status: a two-sample Mendelian randomization study

Abstract

Background: Epidemiological evidence indicates a high correlation and comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and Restless Legs Syndrome (RLS).

Objective: We aimed to investigate the causal relationship and shared genetic architecture between ADHD and RLS, as well as explore potential causal associations between both disorders and peripheral iron status.

Methods: We performed two-sample Mendelian randomization (MR) analyses using summary statistics from genome-wide meta-analyses of ADHD, RLS, and peripheral iron status (serum iron, ferritin, transferrin saturation, and total iron binding capacity). Additionally, we employed linkage disequilibrium score regression (LDSC) to assess genetic correlations between ADHD and RLS using genetic data.

Results: Our MR results supports a causal effect from ADHD (as exposure) to RLS (as outcome) (inverse variance weighted OR = 1.20, 95% CI: 1.08-1.34, p = 0.001). Conversely, we found no a causal association from RLS to ADHD (inverse variance weighted OR = 1.04, 95% CI: 0.99-1.09, p = 0.11). LDSC analysis did not detect a significant genetic correlation between RLS and ADHD (Rg = 0.3, SE = 0.16, p = 0.068). Furthermore, no evidence supported a causal relationship between peripheral iron deficiency and the RLS or ADHD onset. However, RLS may have been associated with a genetic predisposition to reduced serum ferritin levels (OR = 1.20, 95% CI: 1.00-1.04, p = 0.047).

Conclusion: This study suggests that ADHD is an independent risk factor for RLS, while RLS may confer a genetic predisposition to reduced serum ferritin levels.

Limitations: The GWAS summary data utilized originated from populations of European ancestry, limiting the generalizability of conclusions to other populations.

Clinical implications: The potential co-occurrence of RLS in individuals with ADHD should be considered during diagnosis and treatment. Moreover, iron supplementation may be beneficial for alleviating RLS symptoms.

Keywords: ADHD; LDSC; MR; RLS; attention deficit hyperactivity disorder; iron status; restless legs syndrome.

Figure 1

Mendelian randomization study results are displayed in forest plots to assess the potential causal relationship between ADHD and RLS. (A) The forest plot displays point estimates of ADHD exposure on RLS (outcome). After excluding pleiotropic, heterogeneous, incompatible, and palindromic SNPs, 23 index SNPs remained to construct instrument variables. (B) The forest plot displays point estimates of RLS exposure on ADHD (outcome). After excluding pleiotropic, heterogeneous, incompatible, and palindromic SNPs, 11 index SNPs remained to construct instrument variables. The black dots indicate the causal estimate (b = log odds ratio) of each SNP on the risk of ADHD. The red dots indicate the combined causal estimate of all SNPs using MR Egger and IVW methods. Horizontal lines represent 95% CI.