Long-Term Treatment of Narcolepsy and Idiopathic Hypersomnia with Low-Sodium Oxybate.

Narcolepsy and idiopathic hypersomnia are chronic conditions that negatively affect alertness, mental and physical energy, functioning, and quality of life (QoL). Calcium, magnesium, potassium, and sodium oxybates (low-sodium oxybate; LXB) is an oxybate formulation with 92% less sodium than sodium oxybate (SXB; a treatment for narcolepsy) and the same active moiety. LXB is approved in the US for treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age or older with narcolepsy, and idiopathic hypersomnia in adults. In Phase 3 clinical trials, LXB exhibited a safety profile consistent with that of SXB in narcolepsy. Besides continued efficacy in treating symptoms, potential benefits of long-term LXB treatment include flexible optimization of dosing and regimen, improvement of QoL and functioning, weight loss, and (relative to SXB in narcolepsy) health benefits of reduced sodium content. Dosing of LXB is twice nightly (for narcolepsy) or once or twice nightly (for idiopathic hypersomnia) based on patient characteristics and response, and individualized titration can be leveraged over the long term as a patient's life circumstances change. Patients with narcolepsy transitioning from SXB initiate LXB at the same dose, and most patients require no further changes to achieve similar efficacy and tolerability. Improvements in functioning and QoL with LXB treatment could have cascading positive effects in multiple domains, particularly in younger patients. In clinical trials, LXB was associated with weight loss in both narcolepsy (in which obesity is a well-established comorbidity) and idiopathic hypersomnia, only occasionally leading participants to be underweight. As both narcolepsy and idiopathic hypersomnia are associated with increased risk of cardiometabolic and cardiovascular comorbidities, limiting medication-related sodium intake with LXB may have significant health benefits, although this has not yet been verified prospectively due to the prolonged follow-up required. LXB is a promising long-term treatment for narcolepsy and idiopathic hypersomnia.

Narcolepsy and idiopathic hypersomnia are disorders that make people feel very sleepy. Low-sodium oxybate (LXB) is a medicine for these disorders. Doctors think LXB works on parts of the brain that keep people awake. LXB may quiet those brain parts down at night by reducing their electrical activity, which helps people sleep better. LXB wears off by the morning, so people can wake up normally and feel more alert the next day. LXB has less sodium (which is part of salt) than a medicine called sodium oxybate. Sodium oxybate has been used for narcolepsy for more than 20 years. LXB has several benefits. First, LXB may be healthier than medicines that contain a lot of sodium, such as a high-sodium oxybate. This is because sodium can increase blood pressure and risk of heart disease. Second, LXB can be taken twice each night for narcolepsy, or once or twice each night for idiopathic hypersomnia. This depends on a person's lifestyle, how well the medicine is working, and side effects. Third, people taking LXB are more able to work and do other activities and have better quality of life. Finally, people taking LXB may lose weight. This can help overweight or obese people.

Impairment in Functioning and Quality of Life in Patients with Idiopathic Hypersomnia: The Real World Idiopathic Hypersomnia Outcomes Study (ARISE).

Purpose: Idiopathic hypersomnia is a debilitating neurologic sleep disorder characterized by excessive daytime sleepiness, sleep inertia, and prolonged sleep. Its impact on patients' quality of life and daily functioning has not been fully elucidated. The Real World Idiopathic Hypersomnia Outcomes Study (ARISE) evaluated the daily functioning, relationships, cognition, emotional well-being, and productivity/employment of participants with idiopathic hypersomnia. Patients and Methods: ARISE was a US-based virtual cross-sectional survey comprising multiple patient-reported outcome measures (Functional Outcomes of Sleep Questionnaire, short version [FOSQ-10], Quality of Life in Neurological Disorders [Neuro-QoL] Social Roles and Stigma domains, British Columbia Cognitive Complaints Inventory [BC-CCI], Patient Health Questionnaire [PHQ-9], and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem [WPAI:SHP]). Participants were adults 21-65 years of age with idiopathic hypersomnia. Data were analyzed for all participants and for subgroups with/without long sleep time (LST; self-reported sleep ≥11 hours in 24 hours). Results: Of 75 participants enrolled, most were female (81.3%) and the mean (SD) age was 34.1 (10.7) years. Participants' scores on the FOSQ-10 (mean [SD] score: 10.7 [2.8]) and the Neuro-QoL Social Roles (43.4 [4.2]) and Stigma (57.3 [5.9]) domains reflected impairments in daily functioning and quality of life. More than half of participants reported moderate to severe cognitive complaints (BC-CCI; 62.7%) and moderate to severe depressive symptoms (PHQ-9; 66.7%). Scores on the WPAI:SHP showed substantial impairments in absenteeism, presenteeism, overall work productivity, and overall regular daily activity (mean percent [SD]: 12.3 [23.6], 47.6 [22.7], 51.4 [24.7], and 64.0 [21.9], respectively). These considerable impairments were found in participants with and without LST. Conclusion: ARISE participants with idiopathic hypersomnia demonstrated poor quality of life and impaired functioning across multiple symptom domains.

The genetic etiology of periodic limb movement in sleep.

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, ß = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, ß = 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.

Sleep and seizure risk in epilepsy: bed and wake times are more important than sleep duration.

Sleep duration, sleep deprivation and the sleep-wake cycle are thought to play an important role in the generation of epileptic activity and may also influence seizure risk. Hence, people diagnosed with epilepsy are commonly asked to maintain consistent sleep routines. However, emerging evidence paints a more nuanced picture of the relationship between seizures and sleep, with bidirectional effects between changes in sleep and seizure risk in addition to modulation by sleep stages and transitions between stages. We conducted a longitudinal study investigating sleep parameters and self-reported seizure occurrence in an ambulatory at-home setting using mobile and wearable monitoring. Sixty subjects wore a Fitbit smartwatch for at least 28 days while reporting their seizure activity in a mobile app. Multiple sleep features were investigated, including duration, oversleep and undersleep, and sleep onset and offset times. Sleep features in participants with epilepsy were compared to a large (n = 37 921) representative population of Fitbit users, each with 28 days of data. For participants with at least 10 seizure days (n = 34), sleep features were analysed for significant changes prior to seizure days. A total of 4956 reported seizures (mean = 83, standard deviation = 130) and 30 485 recorded sleep nights (mean = 508, standard deviation = 445) were included in the study. There was a trend for participants with epilepsy to sleep longer than the general population, although this difference was not significant. Just 5 of 34 participants showed a significant difference in sleep duration the night before seizure days compared to seizure-free days. However, 14 of 34 subjects showed significant differences between their sleep onset (bed) and/or offset (wake) times before seizure occurrence. In contrast to previous studies, the current study found undersleeping was associated with a marginal 2% decrease in seizure risk in the following 48 h (P < 0.01). Nocturnal seizures were associated with both significantly longer sleep durations and increased risk of a seizure occurring in the following 48 h. Overall, the presented results demonstrated that day-to-day changes in sleep duration had a minimal effect on reported seizures, while patient-specific changes in bed and wake times were more important for identifying seizure risk the following day. Nocturnal seizures were the only factor that significantly increased the risk of seizures in the following 48 h on a group level. Wearables can be used to identify these sleep-seizure relationships and guide clinical recommendations or improve seizure forecasting algorithms.

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response.

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea−hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Genetic risk for subjective reports of insomnia associates only weakly with polygraphic measures of insomnia in 2,770 adults.

STUDY OBJECTIVES: Subjective insomnia complaints and objective sleep changes are mostly studied outside of clinical trial studies. In this study, we tested whether 240 genetic variants associated with subjectively reported insomnia were also associated with objective insomnia parameters extracted from polysomnographic recordings in three studies. METHODS: The study sample (total n = 2,770) was composed of the Wisconsin Sleep Cohort (n = 1,091) and the Osteoporotic Fractures in Men (n = 1,026) study, two population-based studies, and the Stanford Sleep Cohort, a sleep center patient-based sample (n = 653). Seven objective polysomnographic features related to insomnia defined outcome variables, with each variant allele serving as predictor. Meta-regression was performed, accounting for common confounders as well as variance differences between studies. Additionally, a normalized genetic risk score was generated for each subject to serve as a predictor variable in separate linear mixed models assessing objective insomnia features. RESULTS: After correction for multiple testing, single-nucleotide polymorphisms associated with subjective insomnia were not significantly associated with 6 of 7 objective sleep measures. Only periodic limb movement index was significantly associated with rs113851554 (MEIS1), as found in previous studies. The normalized genetic risk score was only weakly associated with arousal index and duration of wake after sleep onset. CONCLUSIONS: Our findings suggest that subjective insomnia does not have a strong genetic signature mapping onto objective (polysomnographic) sleep variables. CITATION: Foldager J, Peppard PE, Hagen EW, et al. Genetic risk for subjective reports of insomnia associates only weakly with polygraphic measures of insomnia in 2,770 adults. J Clin Sleep Med. 2022;18(1):21-29.

Active and Distance Learning in Neuroscience Education.

With social distancing and uncertainty about the complete re-opening of laboratories and campuses, there is a pressing need for a more flexible educational experience. Seizing this opportunity to integrate active learning into adaptive curricula can fast-forward neuroscience education at every level.

Active Learning in Psychiatry Education: Current Practices and Future Perspectives.

Over the past few decades, medical education has seen increased interest in the use of active learning formats to engage learners and promote knowledge application over knowledge acquisition. The field of psychiatry, in particular, has pioneered a host of novel active learning paradigms. These have contributed to our understanding of the role of andragogy along the continuum of medical education, from undergraduate to continuing medical education. In an effort to frame the successes and failures of various attempts at integrating active learning into healthcare curricula, a group of educators from the A. B. Baker Section on Neurological Education from the American Academy of Neurology reviewed the state of the field in its partner field of medical neuroscience. Herein we provide a narrative review of the literature, outlining the basis for implementing active learning, the novel formats that have been used, and the lessons learned from qualitative and quantitative analysis of the research that has been done to date. While preparation time seems to present the greatest obstacle to acceptance from learners and educators, there is generally positive reception to the new educational formats. Additionally, most assessments of trainee performance have suggested non-inferiority (if not superiority). However, occasional mixed findings point to a need for better assessments of the type of learning that these new formats engender: knowledge application rather than acquisition. Moreover, this field is relatively nascent and, in order to ascertain how best to integrate active learning into psychiatry education, a framework for quantitative outcome assessments is needed going forward.

Study design considerations for sleep-disordered breathing devices.

None: In recent years, sleep-disordered breathing (SDB) has been recognized as a prevalent but under-diagnosed condition in adults and has prompted the need for new and better diagnostic and therapeutic options. To facilitate the development and availability of innovative, safe and effective SDB medical device technologies for patients in the United States, the US Food and Drug Administration collaborated with six SDB-related professional societies and a consumer advocacy organization to convene a public workshop focused on clinical investigations of SDB devices. Sleep medicine experts discussed appropriate definitions of terms used in the diagnosis and treatment of SDB, the use of home sleep testing versus polysomnography, clinical trial design issues in studying SDB devices, and current and future trends in digital health technologies for diagnosis and monitoring SDB. The panel's breadth of clinical expertise and experience across medical specialties provided useful and important insights regarding clinical trial designs for SDB devices.

High-Resolution Spectral Sleep Analysis Reveals a Novel Association Between Slow Oscillations and Memory Retention in Elderly Adults.

Objective: In recognition of the mixed associations between traditionally scored slow wave sleep and memory, we sought to explore the relationships between slow wave sleep, electroencephalographic (EEG) power spectra during sleep and overnight verbal memory retention in older adults. Design, Setting, Participants, and Measurements: Participants were 101 adults without dementia (52% female, mean age 70.3 years). Delayed verbal memory was first tested in the evening prior to overnight polysomnography (PSG). The following morning, subjects were asked to recall as many items as possible from the same List (overnight memory retention; OMR). Partial correlation analyses examined the associations of delayed verbal memory and OMR with slow wave sleep (SWS) and two physiologic EEG slow wave activity (SWA) power spectral bands (0.5-1 Hz slow oscillations vs. 1-4 Hz delta activity). Results: In subjects displaying SWS, SWS was associated with enhanced delayed verbal memory, but not with OMR. Interestingly, among participants that did not show SWS, OMR was significantly associated with a higher slow oscillation relative power, during NREM sleep in the first ultradian cycle, with medium effect size. Conclusions: These findings suggest a complex relationship between SWS and memory and illustrate that even in the absence of scorable SWS, older adults demonstrate substantial slow wave activity. Further, these slow oscillations (0.5-1 Hz), in the first ultradian cycle, are positively associated with OMR, but only in those without SWS. Our findings raise the possibility that precise features of slow wave activity play key roles in maintaining memory function in healthy aging. Further, our results underscore that conventional methods of sleep evaluation may not be sufficiently sensitive to detect associations between SWA and memory in older adults.

Strategic Considerations for Applying the Flipped Classroom to Neurology Education.

Nowadays, the "flipped classroom" approach is taking the center stage within medical education. However, very few reports on the implementation of the flipped classroom in neurology have been published to date, and this educational model still represents a challenge for students and educators alike. In this article, neurology educators from the American Academy of Neurology's A. B. Baker Section on Neurological Education analyze reports of flipped classroom in other medical/surgical subspecialties, review the current implementation in neurology, and discuss future strategies to flip the neurology curriculum through contextualization of the benefits and the consequences. ANN NEUROL 2020;87:4-9.

Factors Associated with Supportive Care Service Use Among California Alzheimer's Disease Patients and Their Caregivers.

BACKGROUND: Existing literature on factors associated with supportive care service (SCS) use is limited. A better understanding of these factors could help tailor SCS to the needs of frequent users, as well as facilitate targeted outreach to populations that underutilize available services. OBJECTIVE: To investigate the prevalence of SCS use and to identify factors associated with, and barriers to, service use. METHODS: California Alzheimer's Disease Center patients with AD (n = 220) participated in the study from 2006-2009. Patients and their caregivers completed assessments to determine SCS use. Cognitive, functional, and behavioral status of the patients were also assessed. A two-part hurdle analysis identified 1) factors associated with any service use and 2) service use frequency among users. RESULTS: Forty percent of participants reported using at least one SCS. Patients with more impaired cognition and activities of daily living and more of the following: total number of medications, comorbid medical conditions, and years of education were more likely to use any SCS (p < 0.05). Factors associated with more frequent SCS use included younger age, more years of education, older age of AD onset, female gender, and having a spouse or relative for a caregiver (p < 0.05). Caregivers frequently indicated insufficient time as a reason for not receiving enough services. CONCLUSION: Factors associated with any SCS use mostly differed from those associated with SCS frequency, suggesting different characteristics between those who initiate versus those who continue SCS use. Our findings highlight the importance of targeted education on services and identifying barriers to long-term SCS use.

Education Research: Flipped classroom in neurology: Principles, practices, and perspectives.

How to most effectively deliver a large amount of information in an engaging environment that encourages critical thinking is a question that has long plagued educators. With ever-increasing demands on both resident and faculty time, from shrinking duty hours to increased patient complexity, combined with the exponential growth of medical knowledge and unequal access to the spectrum of neurologic subspecialties around the country, this question has become especially pertinent to neurology residency training. A team of educators from the American Academy of Neurology's A.B. Baker Section on Neurological Education sought to review the current evidence regarding the implementation of the flipped classroom format. This educational model has only recently been applied to health care education along the training continuum, and a small collection of articles has, so far, used disparate methods of curricular implementation and assessment. While the feedback from learners is generally positive, a number of obstacles to implementation exist, most notably learner time commitments. These are presented with discussion of potential solutions along with suggestions for future studies.

Daylight saving time transitions are not associated with increased seizure incidence.

OBJECTIVE: Given the known association of daylight saving time (DST) transitions with increased risk of accidents, heart attack, and stroke, we aimed to determine whether seizures, which are reportedly influenced by sleep and circadian disruption, also increased in frequency following the transition into DST. METHODS: Using Seizure Tracker's self-reported data from 12 401 individuals from 2008-2016, 932 717 seizures were assessed for changes in incidence in relation to DST transitions. Two methods of standardization-z scores and unit-scaled rate ratios (RRs)-were used to compare seizure propensities following DST transitions to other time periods. RESULTS: As a percentile relative to all other weeks in a given year, absolute seizure counts in the week of DST fell below the median (DST seizure percentiles mean ± SD: 19.68 ± 16.25, P = 0.01), which was concordant with weekday-specific comparisons. Comparatively, RRs for whole-week (1.06, 95% confidence interval [CI] 1.02-1.10, P = 0.0054) and weekday-to-weekday (RR range 1.04-1.16, all P < 0.001) comparisons suggested a slightly higher incidence of seizures in the DST week compared to all other weeks of the year. However, examining the similar risk of the week preceding and following the DST-transition week revealed no significant weekday-to-weekday differences in seizure incidence, although there was an unexpected, modestly decreased seizure propensity in the DST week relative to the whole week prior (RR 0.94, 95% CI 0.91-0.96, P < 0.001). SIGNIFICANCE: Despite expectations that circadian and sleep disruption related to DST transitions would increase the incidence of seizures, we found little substantive evidence for such an association in this large, longitudinal cohort. Although large-scale observational/epidemiologic cohorts can be effective at answering such questions, additional covariates (eg, sleep duration, seizure type, and so on) that may underpin the association were not able available, so the association has not definitively been ruled out.

Non-invasive machine learning estimation of effort differentiates sleep-disordered breathing pathology.

OBJECTIVE: Obstructive sleep-disordered breathing (SDB) events, unlike central events, are associated with increased respiratory effort. Esophageal pressure (P es) monitoring is the gold standard for measuring respiratory effort, but it is typically poorly tolerated because of its invasive nature. The objective was to investigate whether machine learning can be applied to routinely collected non-invasive, polysomnography (PSG) measures to accurately model peak negative P es. APPROACH: One thousand one hundred and nineteen patients from the Stanford Sleep Clinic with PSGs containing P es served as the sample. The selected non-invasive PSG signals included nasal pressure, oral airflow, thoracoabdominal effort, and snoring. A long short-term memory neural network was implemented to achieve a context-based mapping between the non-invasive features and the P es values. A hold-out dataset served as a prospective validation of the algorithm without needing to undertake a costly new study with the impractically invasive P es. MAIN RESULTS: The median difference between the measured and predicted P es was 0.61 cmH2O with an interquartile range (IQR) of 2.99 cmH2O and 5th and 95th percentiles of -5.85 cmH2O and 5.47 cmH2O, respectively. The model performed well when compared to actual esophageal pressure signal (ρ median = 0.581, p  = 0.01; IQR = 0.298; ρ 5% = 0.106; ρ 95% = 0.843). SIGNIFICANCE: A significant difference in predicted P es was shown between normal breathing and all obstructive SDB events; whereas, central apneas did not significantly differ from normal breathing. The developed system may be used as a tool for quantifying respiratory effort from the existing clinical practice of PSG without the need for P es, improving characterization of SDB events as obstructive or not.

Neurologic and neuroscience education: Mitigating neurophobia to mentor health care providers.

Neurologic disorders are among the most frequent causes of morbidity and mortality in the United States. Moreover, the current shortfall of neurologists is expected to worsen over the coming decade. As a consequence, many patients with neurologic disorders will be treated by physicians and primary care providers without formal neurologic training. Furthermore, a pervasive and well-described fear of neurology, termed neurophobia, has been identified in medical student cohorts, residents, and among general practitioners. In this article, members of the American Academy of Neurology A.B. Baker Section on Neurological Education review current guidelines regarding neurologic and neuroscience education, contextualize the genesis and the negative consequences of neurophobia, and provide strategies to mitigate it for purposes of mentoring future generations of health care providers.

Periodic limb movements in sleep: Prevalence and associated sleepiness in the Wisconsin Sleep Cohort.

OBJECTIVES: Periodic limb movements in sleep (PLMS) are thought to be prevalent in elderly populations, but their impact on quality of life remains unclear. We examined the prevalence of PLMS, impact of age on prevalence, and association between PLMS and sleepiness. METHODS: We identified limb movements in 2335 Wisconsin Sleep Cohort polysomnograms collected over 12 years. Prevalence of periodic limb movement index (PLMI) ≥15 was calculated at baseline (n = 1084). McNemar's test assessed changes in prevalence over time. Association of sleepiness and PLMS evaluated using linear mixed modeling and generalized estimating equations. Models adjusted for confounders. RESULTS: Prevalence of PLMI ≥15 at baseline was 25.3%. Longitudinal prevalence increased significantly with age (p = 2.97 × 10-14). Sleepiness did not differ significantly between PLMI groups unless stratified by restless legs syndrome (RLS) symptoms. The RLS+/PLM+ group was sleepier than the RLS+/PLM- group. Multiple Sleep Latency Test trended towards increased alertness in the RLS-/PLM+ group compared to RLS-/PLM-. CONCLUSIONS: A significant number of adults have PLMS and prevalence increased with age. No noteworthy association between PLMI category and sleepiness unless stratified by RLS symptoms. SIGNIFICANCE: Our results indicate that RLS and PLMS may have distinct clinical consequences and interactions that can help guide treatment approach.

Genetic Basis of Chronotype in Humans: Insights From Three Landmark GWAS.

Study Objectives: Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related illnesses. Family studies indicate that chronotype is a heritable trait, thus directing attention toward its genetic basis. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWAS), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. This review discusses the findings of these landmark GWASs in the context of prior research. Methods: We systematically reviewed and compared methodological and analytical approaches and results across the three GWASs of chronotype. Results: A good deal of consistency was observed across studies with 9 genes identified in 2 of the 3 GWASs. Several genes previously unknown to influence chronotype were identified. Conclusions: GWAS is an important tool in identifying common variants associated with the complex chronotype phenotype, the findings of which can supplement and guide molecular science. Future directions in model systems and discovery of rare variants are discussed.