Dataset Information

Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.

ABSTRACT: STUDY OBJECTIVES:To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS). SETTING:Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research. PATIENTS:Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012). DESIGN AND INTERVENTIONS:A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 × 10(-3)). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response. MEASUREMENTS AND RESULTS:Prevalence of PLMI ? 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations. CONCLUSIONS:Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.

SUBMITTER: Moore H

PROVIDER: S-EPMC4153066 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.

Moore Hyatt H Winkelmann Juliane J Lin Ling L Finn Laurel L Peppard Paul P Mignot Emmanuel E

Sleep 20140901 9

<h4>Study objectives</h4>To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).<h4>Setting</h4>Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.<h4>Patients</h4>Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).< ...[more]

PMID: 25142570

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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.

Dataset Information

Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.

Publications

Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.

Similar Datasets

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