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      Biological and clinical insights from genetics of insomnia symptoms

      research-article
      1 , 2 , 3 , 40 , 4 , 40 , 1 , 3 , 4 , 1 , 3 , 5 , 6 , 7 , 8 , 8 , 9 , 10 , 3 , 11 , 12 , 13 , 14 , 1 , 3 , 15 , 1 , 15 , 16 , 17 , 4 , 18 , 3 , 11 , 12 , 1 , 3 , 1 , 3 , 5 , 6 , 19 , 20 , 21 , 22 , 18 , 23 , 24 , 25 , 3 , 11 , 12 , 26 , 4 , 27 , 26 , 28 , 29 , 30 , HUNT All In Sleep, 8 , 26 , 9 , 32 , 33 , 34 , 35 , 36 , 21 , 18 , 37 , 8 , 10 , 8 , 13 , 38 , 4 , 13 , 14 , 41 , 18 , 39 , 41 , 4 , 41 , 1 , 2 , 3 , 41 , *
      Nature genetics
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank ( n = 453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study ( n = 14,923 cases, 47,610 controls), physician-diagnosed insomnia in Partners Biobank ( n = 2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank ( n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms and subjective well-being.

          Editorial summary:

          Genome-wide association analyses identify 57 loci associated with insomnia symptoms and evidence of shared genetic architecture between insomnia and cardio-metabolic, behavioral, psychiatric and reproductive traits.

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          Most cited references61

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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            Is Open Access

            Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

            Enrichment analysis is a popular method for analyzing gene sets generated by genome-wide experiments. Here we present a significant update to one of the tools in this domain called Enrichr. Enrichr currently contains a large collection of diverse gene set libraries available for analysis and download. In total, Enrichr currently contains 180 184 annotated gene sets from 102 gene set libraries. New features have been added to Enrichr including the ability to submit fuzzy sets, upload BED files, improved application programming interface and visualization of the results as clustergrams. Overall, Enrichr is a comprehensive resource for curated gene sets and a search engine that accumulates biological knowledge for further biological discoveries. Enrichr is freely available at: http://amp.pharm.mssm.edu/Enrichr.
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              Is Open Access

              UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

              Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                28 January 2019
                25 February 2019
                March 2019
                25 August 2019
                : 51
                : 3
                : 387-393
                Affiliations
                [1 ]Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
                [2 ]Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
                [3 ]Broad Institute, Cambridge, Massachusetts, USA.
                [4 ]Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
                [5 ]Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
                [6 ]Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
                [7 ]Netherlands eScience Center, Amsterdam, The Netherlands.
                [8 ]K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Norway.
                [9 ]FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway.
                [10 ]Division of Clinical Neuroscience, Oslo University Hospital and University of Oslo, Oslo, Norway.
                [11 ]Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
                [12 ]Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
                [13 ]MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
                [14 ]Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
                [15 ]College of Science, Northeastern University, Boston, Massachusetts, USA.
                [16 ]Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
                [17 ]The Farr Institute of Health Informatics Research, University College London, London, UK.
                [18 ]Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
                [19 ]Department of Mathematics, Aston University, Birmingham, UK.
                [20 ]Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
                [21 ]Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
                [22 ]Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
                [23 ]Department of Psychiatry, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
                [24 ]School of Social and Community Medicine, University of Bristol, Bristol, UK.
                [25 ]Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
                [26 ]Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
                [27 ]Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
                [28 ]Cluster for Systems Neurology (SyNergy), Munich, Germany.
                [29 ]Institute of Human Genetics, Technische Universität München, Munich, Germany.
                [30 ]Chair of Neurogenetics, Technische Universität München, Munich, Germany.
                [31 ]A list of members and affiliations appears at the end of the paper.
                [32 ]Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
                [33 ]Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
                [34 ]Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
                [35 ]Departments of Medicine, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
                [36 ]Clinic for Psychiatry and Psychotherapy, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
                [37 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX37LE/NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
                [38 ]Department of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
                [39 ]Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
                [40 ]These authors contributed equally to this work.
                [41 ]These authors jointly directed this project.
                [42 ]FORMI, Oslo University Hospital, Oslo, Norway.
                [43 ]Department of Health Promotion, Norwegian Institute of Public Health, Bergen, Norway.
                [44 ]Institute for Mental Health, Faculty of Medicine, Norwegian Univeristy of Science and Technology, Trondheim, Norway.
                [45 ]Department of Research and Development, Division of Psychiatry, St. Olavs University Hospital, Trondheim, Norway.
                [46 ]Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
                [47 ]Oslo University Hospital, Department of Neurology, Oslo, Norway.
                [48 ]Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
                [49 ]Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim, Norway.
                Author notes

                Author Contributions

                The study was designed by J.M.L., S.E.J., A.R.W., H.S.D., V.V.H., K.H., B.M.B., L.B.S., B.W., K.A., H.W., S.G.A., A.S.L., D.W.R., T.M.F., M.N.W., D.A.L., M.K.R., and R.S. J.M.L., S.J., A.R.W., H.S.D., V.V.H., R.B., J.T., K.A., H.W., Y.S., K.P., S.M.P., J.W.W., T.M.F., D.A.L., M.K.R., M.N.W., and R.S. participated in acquisition, analysis and/or interpretation of data. J.M.L., H.S.D., B.M.B., L.B.S., H.W. and R.S. wrote the manuscript and all co-authors reviewed and edited the manuscript, before approving its submission. R.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

                Article
                NIHMS1519714
                10.1038/s41588-019-0361-7
                6415688
                30804566
                6a149fe8-8327-4501-a858-84c985ce635c

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