Genome-wide association study of restless legs syndrome in end-stage renal disease

Restless legs syndrome (RLS) is predominantly idiopathic (iRLS), with a prevalence of 2%-10% in Europe. In end-stage renal disease patients (ESRD), uremic RLS (uRLS) is substantially more prevalent, with estimates of 24%-28%. Its pathophysiology has not been fully uncovered. Therefore, we investigated potential genetic and phenotypic risk factors for uRLS.

We performed case-control genome-wide association studies (GWAS) on ESRD patients with and without RLS from two German and one Greek ESRD study populations (cases/controls: 186/356, 80/176, 134/357). We applied a polygenic risk score (PRS) for iRLS to four groups: uRLS cases, uremic controls, a group of iRLS cases and European 1000G individuals. Additionally, we investigated RLS associations with phenotype data available in one German dataset.

No SNP reached genome-wide significance in any single dataset or meta-analyses. The mean iRLS PRS was significantly higher in uRLS cases compared to uremic controls (p = 9.47e-10) and European 1000G individuals (p = 9.93e-6) and significantly smaller compared to iRLS cases (p = 4.84e-5). Among 164 available lead SNPs at known RLS risk loci, rs113851554 at the MEIS1 locus, the strongest known iRLS-associated variant, was significant after Bonferroni correction (0.05/164 = 3.05e-4) in the German uremic meta-analysis (p = 5.73e-5). Two loci rs36127502 and rs5769388, previously not associated with RLS, show suggestive significance (p = 1.37e-7, p = 1.92e-7) in a meta-analysis combining the three GWAS datasets. Regular smoking and parathormone levels were nominally associated with RLS in ESRD.

Our findings indicate that uRLS and iRLS share a substantial part of their genetic architecture, while also pointing to candidate signals specific to uRLS.