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      Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

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      Nature Communications
      Nature Publishing Group UK
      Sleep, Genome-wide association studies, Sleep disorders

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          Abstract

          Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.

          Abstract

          A main symptom of chronic insufficient sleep is excessive daytime sleepiness. Here, Wang et al. report 42 genome-wide significant loci for self-reported daytime sleepiness in 452,071 individuals from the UK Biobank that cluster into two biological subtypes of either sleep propensity or sleep fragmentation.

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          Most cited references34

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          Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression

          Abstract Background Summary data furnishing a two-sample Mendelian randomization (MR) study are often visualized with the aid of a scatter plot, in which single-nucleotide polymorphism (SNP)–outcome associations are plotted against the SNP–exposure associations to provide an immediate picture of the causal-effect estimate for each individual variant. It is also convenient to overlay the standard inverse-variance weighted (IVW) estimate of causal effect as a fitted slope, to see whether an individual SNP provides evidence that supports, or conflicts with, the overall consensus. Unfortunately, the traditional scatter plot is not the most appropriate means to achieve this aim whenever SNP–outcome associations are estimated with varying degrees of precision and this is reflected in the analysis. Methods We propose instead to use a small modification of the scatter plot—the Galbraith Radial plot—for the presentation of data and results from an MR study, which enjoys many advantages over the original method. On a practical level, it removes the need to recode the genetic data and enables a more straightforward detection of outliers and influential data points. Its use extends beyond the purely aesthetic, however, to suggest a more general modelling framework to operate within when conducting an MR study, including a new form of MR-Egger regression. Results We illustrate the methods using data from a two-sample MR study to probe the causal effect of systolic blood pressure on coronary heart disease risk, allowing for the possible effects of pleiotropy. The Radial plot is shown to aid the detection of a single outlying variant that is responsible for large differences between IVW and MR-Egger regression estimates. Several additional plots are also proposed for informative data visualization. Conclusions The Radial plot should be considered in place of the scatter plot for visualizing, analysing and interpreting data from a two-sample summary data MR study. Software is provided to help facilitate its use.
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            The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.

            Narcolepsy is a disabling sleep disorder affecting humans and animals. It is characterized by daytime sleepiness, cataplexy, and striking transitions from wakefulness into rapid eye movement (REM) sleep. In this study, we used positional cloning to identify an autosomal recessive mutation responsible for this sleep disorder in a well-established canine model. We have determined that canine narcolepsy is caused by disruption of the hypocretin (orexin) receptor 2 gene (Hcrtr2). This result identifies hypocretins as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients.
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              Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates

              Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration (p < 5 × 10−8; 43 loci at p < 6 × 10−9). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10−4), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis (n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.
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                Author and article information

                Contributors
                rsaxena@partners.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                13 August 2019
                13 August 2019
                2019
                : 10
                : 3503
                Affiliations
                [1 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Sleep and Circadian Disorders, , Brigham and Women’s Hospital and Harvard Medical School, ; Boston, MA USA
                [2 ]GRID grid.66859.34, Program in Medical and Population Genetics, , Broad Institute, ; Cambridge, MA USA
                [3 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Center for Genomic Medicine, , Massachusetts General Hospital, ; Boston, MA USA
                [4 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Anesthesia, Critical Care and Pain Medicine, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [5 ]ISNI 0000 0004 1936 8024, GRID grid.8391.3, Genetics of Complex Traits, , University of Exeter Medical School, ; Exeter, United Kingdom
                [6 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Psychiatry and Behavioral Sciences, , Stanford University, ; Palo Alto, CA USA
                [7 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Institute for Molecular Medicine Finland, , University of Helsinki, ; Helsinki, Finland
                [8 ]GRID grid.454309.f, Netherlands eScience Center, ; Amsterdam, Netherlands
                [9 ]ISNI 0000 0001 1516 2393, GRID grid.5947.f, K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, , Norwegian University of Science and Technology, ; Trondheim, Norway
                [10 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, MRC Integrative Epidemiology Unit at the University of Bristol, ; Bristol, UK
                [11 ]ISNI 0000 0004 0627 3560, GRID grid.52522.32, Department of Thoracic and Occupational Medicine, St. Olavs Hospital, , Trondheim University Hospital, ; Trondheim, Norway
                [12 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Division of Clinical Neuroscience, , Oslo University Hospital and University of Oslo, ; Oslo, Norway
                [13 ]ISNI 0000 0001 1013 0499, GRID grid.14758.3f, Genomics and Biomarkers Unit, , National Institute for Health and Welfare, ; Helsinki, Finland
                [14 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Psychiatry and SleepWell Research Program, Faculty of Medicine, , University of Helsinki and Helsinki University Central Hospital, ; Helsinki, Finland
                [15 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Institute for Molecular Medicine FIMM, , HiLIFE, University of Helsinki, ; Helsinki, Finland
                [16 ]ISNI 0000 0001 2173 3359, GRID grid.261112.7, Northeastern University College of Science, ; Boston, MA USA
                [17 ]ISNI 0000000121662407, GRID grid.5379.8, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, , The University of Manchester, ; Manchester, UK
                [18 ]GRID grid.412886.1, The George Alleyne Chronic Disease Research Centre, Caribbean Institute for Health Research, , University of the West Indies, ; Cave Hill, Barbados
                [19 ]ISNI 0000000121662407, GRID grid.5379.8, Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, , University of Manchester, ; Manchester, UK
                [20 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Population Health Sciences, Bristol Medical School, , University of Bristol, ; Bristol, UK
                [21 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, , University of Oxford, ; Oxford, UK
                [22 ]ISNI 0000 0004 0376 4727, GRID grid.7273.1, Department of Mathematics, , Aston University, ; Birmingham, UK
                [23 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Media Lab, , Massachusetts Institute of Technology, ; Cambridge, MA USA
                [24 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, School of Social and Community Medicine, , University of Bristol, ; Bristol, UK
                [25 ]GRID grid.5963.9, Clinic for Psychiatry and Psychotherapy, Medical Centre, , University of Freiburg, ; Freiburg, Germany
                [26 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Department of Population and Quantitative Health Sciences, , Case Western Reserve University, ; Cleveland, OH USA
                [27 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Public Health, , University of Helsinki, ; Helsinki, Finland
                [28 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Internal Medicine, Division of Cardiology, , University of Michigan, ; Ann Arbor, MI USA
                [29 ]ISNI 0000 0001 2306 7492, GRID grid.8348.7, NIHR Oxford Biomedical Research Centre, , John Radcliffe Hospital, ; Oxford, OX39DU UK
                [30 ]ISNI 0000 0004 0417 0074, GRID grid.462482.e, Manchester Diabetes Centre, Manchester University NHS Foundation Trust, , Manchester Academic Health Science Centre, ; Manchester, UK
                [31 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Department of Sleep Medicine, , Beth Israel Deaconess Medical Center, ; Boston, MA USA
                Author information
                http://orcid.org/0000-0002-1486-7495
                http://orcid.org/0000-0003-0153-922X
                http://orcid.org/0000-0002-1650-679X
                http://orcid.org/0000-0003-0182-9008
                http://orcid.org/0000-0002-3058-1059
                http://orcid.org/0000-0003-4171-8919
                http://orcid.org/0000-0002-7847-8384
                http://orcid.org/0000-0001-8520-8860
                http://orcid.org/0000-0002-2411-6548
                http://orcid.org/0000-0002-8896-073X
                http://orcid.org/0000-0001-8676-8704
                http://orcid.org/0000-0002-2014-7582
                http://orcid.org/0000-0003-0574-5071
                http://orcid.org/0000-0002-9256-6065
                http://orcid.org/0000-0002-3716-2455
                http://orcid.org/0000-0003-4688-107X
                http://orcid.org/0000-0001-5645-4966
                http://orcid.org/0000-0002-6793-2262
                http://orcid.org/0000-0003-2233-1065
                Article
                11456
                10.1038/s41467-019-11456-7
                6692391
                31409809
                39b36d68-fc01-4c9b-9ef8-5f5b311aa787
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 November 2018
                : 27 June 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);
                Award ID: F32DK102323
                Award ID: R01DK107859
                Award ID: R01DK102696
                Award ID: R01DK105072
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000050, U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI);
                Award ID: T32HL007567
                Award ID: K01HL135405
                Award Recipient :
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                © The Author(s) 2019

                Uncategorized
                sleep,genome-wide association studies,sleep disorders
                Uncategorized
                sleep, genome-wide association studies, sleep disorders

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