A genetic risk factor for periodic limb movements in sleep.

BACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.

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

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.

Correlates of PLMs variability over multiple nights and impact upon RLS diagnosis.

OBJECTIVE: Night-to-night variability of periodic leg movements (PLMs) in restless legs syndrome (RLS) was examined to define the range of intra-subject values, impact upon diagnosing RLS, and clinical correlates. METHODS: Twenty RLS patients were monitored for 10-15 nights using a validated, tri-axial accelerometer worn on the ankle. RESULTS: The mean difference in PLMs index (PLMI) between the lowest and highest night was 25.1/h (range: 3.9-73.8). Inter-subject differences accounted for nearly five times the variance in PLMI relative to between nights within an individual. Based on a single night of recording, PLMI criterion thresholds of 5, 10, and 15/h were exceeded on approximately 70.1%, 51.9% and 34.1% of individual nights among these patients. Based on five randomly sampled nights of recordings, the likelihood that such thresholds were met on at least a single night increased to 91.2%, 80.8% and 62.7%, respectively. Women exhibited greater variability. CONCLUSIONS: Variability in PLMs within RLS subjects was substantial, yet individuals' characteristic PLM level represented a quantitative trait. Variability was unrelated to age or scores on scales of RLS severity, sleepiness, functional status, and mood. A larger number of recording nights increased the likelihood that any criterion was reached.