Dataset Information

The genetic etiology of periodic limb movement in sleep.

ABSTRACT:

Study objectives

Periodic limb movement in sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a genome-wide association study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects.

Methods

The MrOS study and Wisconsin Sleep Cohort Study (N = 1745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using Mendelian randomization.

Results

We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 × 10-12, β = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, β = 0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS.

Conclusions

Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.

SUBMITTER: Edelson JL

PROVIDER: S-EPMC10091093 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

The genetic etiology of periodic limb movement in sleep.

Edelson Jacob L JL Schneider Logan D LD Amar David D Brink-Kjaer Andreas A Cederberg Katie L KL Kutalik Zoltán Z Hagen Erika W EW Peppard Paul E PE Tempaku Priscila Farias PF Tufik Sergio S Evans Daniel S DS Stone Katie K Tranah Greg G Cade Brian B Redline Susan S Haba-Rubio Jose J Heinzer Raphael R Marques-Vidal Pedro P Vollenweider Peter P Winkelmann Juliane J Zou James J Mignot Emmanuel E

Sleep 20230401 4

<h4>Study objectives</h4>Periodic limb movement in sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a genome-wide association study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects.<h4>Methods</h4>The MrOS study and Wisconsin Sleep C ...[more]

PMID: 35670608

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Project description:ObjectiveUsing narrative review techniques, this paper evaluates the evidence for separable underlying patho-mechanisms of periodic limb movements (PLMs) to separable PLM motor patterns and phenotypes, in order to elucidate potential new treatment modalities.BackgroundPeriodic limb movement disorder (PLMD) is estimated to occur in 5-8% of the paediatric population and 4-11% of the general adult population. Due to significant sleep fragmentation, PLMD can lead to functional impairment, including hyperactivity and delayed language development in children, and poor concentration and work performance in adults. Longitudinal data demonstrate that those with PLMD are at greater risk of depression and anxiety, and a 4-fold greater risk of developing dementia. PLMD has been extensively studied over the past two decades, and several key insights into the genetic, pathophysiological, and neural correlates have been proposed. Amongst these proposals is the concept of separable PLM phenotypes, proposed on the basis of nocturnal features such as the ratio of limb movements and distribution throughout the night. PLM phenotype and presentation, however, varies significantly depending on the scoring utilized and the nocturnal features examined, across age, and co-morbid clinical conditions. Furthermore, associations between these phenotypes with major neurologic and psychiatric disorders remain controversial.MethodsIn order to elucidate potential divergent biological pathways that may help clarify important new treatment modalities, this paper utilizes narrative review and evaluates the evidence linking PLM motor patterns and phenotypes with hypothesised underlying patho-mechanisms. Distinctive, underlying patho-mechanisms include: a pure motor mechanism originating in the spinal cord, iron deficiency, dopamine system dysfunction, thalamic glutamatergic hyperactivity, and a more cortical-subcortical interplay. In support of the latter hypothesis, PLM rhythmicity appears tightly linked to the microarchitecture of sleep, not dissimilarly to the apnoeic/hypopneic events seen in obstructive sleep apnea (OSA).ConclusionsThis review closes with a proposal for greater investigation into the identification of potential, divergent biological pathways. To do so would require prospective, multimodal imaging clinical studies which may delineate differential responses to treatment in restless legs syndrome (RLS) without PLMS and PLMS without RLS. This could pave the way toward important new treatment modalities.

Project description:Obstructive sleep apnea syndrome (OSA) and restless legs syndrome (RLS) with periodic limb movement during sleep (PLMS) are two sleep disorders characterized by repetitive respiratory or movement events associated with cortical arousals. We compared the cerebral hemodynamic changes linked to periodic apneas/hypopneas with arousals (AHA) in four OSA-patients with periodic limb movements (PLMA) with arousals in four patients with RLS-PLMS using near-infrared spectroscopy (NIRS). AHA induced homogenous pattern of periodic fluctuations in oxygenated (HbO2) and deoxygenated (HHb) hemoglobin, i.e., the decrease of HbO2 was accompanied by an increase of HHb during the respiratory event and resolved to reverse pattern when cortical arousal started. Blood volume (BV) showed the same pattern as HHb but with relative smaller amplitude in most of the AHA events.These changing patterns were significant as Wilcoxon signed-rank tests gave p < 0.001 when comparing the area under the curve of these hemodynamic parameters to zero. By contrast, in PLMA limb movements induced periodic increments in HbO2 and BV (Wilcoxon signed-rank tests, p < 0.001), but HHb changed more heterogeneously even during the events coming from the same patient. Heart rate (HR) also showed different patterns between AHA and PLMA. It significantly decreased during the respiratory event (Wilcoxon signed-rank test, p < 0.001) and then increased after the occurrence of cortical arousal (Wilcoxon signed-rank test, p < 0.001); while in PLMA HR first increased preceding the occurrence of cortical arousal (Wilcoxon signed-rank test, p < 0.001) and then decreased. The results of this preliminary study show that both AHA and PLMA induce changes in cerebral hemodynamics. The occurrence of cortical arousal is accompanied by increased HR in both events, but by different BV changes (i.e., decreased/increased BV in AHA/PLMA, respectively). HR changes may partially account for the increased cerebral hemodynamics during PLMA; whereas in AHA probable vasodilatation mediated by hypoxia/hypercapnia is more crucial for the post-arousal hemodynamics. The differences between changes of cerebral hemodynamics and HR may indicate different pathological mechanisms behind these two sleep disorder events.

Dataset Information

The genetic etiology of periodic limb movement in sleep.

Study objectives

Methods

Results

Conclusions

Publications

The genetic etiology of periodic limb movement in sleep.

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