Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Abstract

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.

Clinical Utility of Polygenic Risk Score in Sleep Disorder

“…In the study, the higher the PRS in the target sam-ple, the lower the educational attention, and the lower the cognitive function [4]. PRS also showed positive correlations between neuroticism and all body fat, as well as percentage fat in the trunk, legs, and arms, and waist-to-hip ratio [4]. These results are consistent with a study that reported an association between high RLS-PRS and an unhealthy lifestyle [5].…”

“…Although GWAS only provides statistically different variant information between patients and the normal population, PRS allows us to identify the clinical characteristics of each individual or group. In the study, the higher the PRS in the target sam-ple, the lower the educational attention, and the lower the cognitive function [4]. PRS also showed positive correlations between neuroticism and all body fat, as well as percentage fat in the trunk, legs, and arms, and waist-to-hip ratio [4].…”

“…Recently, one restless legs syndrome (RLS) study using PRS was published. PRS was calculated using the GWAS meta-analysis for RLS patients who participated in the UK Biobank [4]. The p-value threshold was set at 0.01 because it had the largest variance.…”

Association Between CLOCK Gene Variants and Restless Legs Syndrome in Koreans

“…[30][31][32] In addition, RLS has been reported to have a strong genetic component. 33,34 Specifically regarding circadian rhythm genes, a study by Jung et al 23 found significant differences in the genotype and haplotype frequencies of CLOCK gene variants between patients with RLS and non-RLS controls in Korean patients with schizophrenia. In the present study, we investigated the association between RLS and CLOCK and NPAS2 polymorphisms in the general Korean population.…”

The Genetics of Sleep Disorders in Children: A Narrative Review

“…RLS may be present in conditions such as iron deficiency, Sickle cell disease, Celiac disease, Osgood-Schlatter disease, Diabetes and Thyroid disease [2]. GWAS in RLS identified several risk loci with functions spanning from neurogenesis (MDGA1, MYT1, NTNG1, SEMA6D), cell-junction organisation (PKP4 and SMAD3) and axon guidance (NTNG1 and SEMA6D) to DNA repair/maintenance (APLF, ASTE1, DIS3, PRMT6, and RNF8) and locomotor behaviour (BTBD9, CLN6, HOXB8, and MEIS1) [42,179,180]. Winkelmann et al were the first to identify the strongest genetic risk factor for RLS in the single nucleotide polymorphisms (SNPs) in the intronics, and rarely coding variants of MEIS1 locus, which encodes for a transcription factor involved in haematopoiesis but also in the neurodevelopment of the proximodistal limb axis [181].…”