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Biological and clinical insights from genetics of insomnia symptoms

View ORCID ProfileJacqueline M Lane, Samuel Jones, View ORCID ProfileHassan S Dashti, Andrew R Wood, Krishna Aragam, Vincent T. van Hees, View ORCID ProfileBen Brumpton, View ORCID ProfileBendik Winsvold, Heming Wang, View ORCID ProfileJack Bowden, Yanwei Song, Krunal Patel, Simon G Anderson, View ORCID ProfileRobin Beaumont, View ORCID ProfileDavid A Bechtold, Brian Cade, View ORCID ProfileSek Kathiresan, View ORCID ProfileMax A Little, View ORCID ProfileAnnemarie I Luik, Andrew S Loudon, View ORCID ProfileShaun Purcell, Rebecca C Richmond, View ORCID ProfileFrank AJL Scheer, Jessica Tyrrell, View ORCID ProfileJohn Winkelman, HUNT All In Sleep, Linn B Strand, View ORCID ProfileJonas B. Nielsen, View ORCID ProfileCristen J. Willer, View ORCID ProfileSusan Redline, View ORCID ProfileKai Spiegelhalder, Simon D Kyle, David W Ray, View ORCID ProfileJohn-Anker Zwart, View ORCID ProfileKristian Hveem, View ORCID ProfileTimothy M Frayling, Deborah Lawlor, View ORCID ProfileMartin K Rutter, View ORCID ProfileMichael N Weedon, View ORCID ProfileRicha Saxena
doi: https://doi.org/10.1101/257956
Jacqueline M Lane
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
3Broad Institute, Cambridge, MA, USA
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Samuel Jones
4Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom
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Hassan S Dashti
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
3Broad Institute, Cambridge, MA, USA
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Andrew R Wood
4Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom
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Krishna Aragam
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
3Broad Institute, Cambridge, MA, USA
5Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Vincent T. van Hees
6Netherlands eScience Center, Amsterdam, The Netherlands
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Ben Brumpton
7K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Norway
8MRC Integrative Epidemiology Unit at the University of Bristol, UK
9Department of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
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Bendik Winsvold
7K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Norway
26FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway
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Heming Wang
3Broad Institute, Cambridge, MA, USA
10Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital
11Division of Sleep Medicine, Harvard Medical School, University of Bristol, UK
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Jack Bowden
8MRC Integrative Epidemiology Unit at the University of Bristol, UK
12Population Health Sciences, Bristol Medical School, University of Bristol, UK
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Yanwei Song
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
13Northeastern University College of Science, 206 Mugar Life Sciences, 360 Huntington Avenue, Boston, MA 02115
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Krunal Patel
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
13Northeastern University College of Science, 206 Mugar Life Sciences, 360 Huntington Avenue, Boston, MA 02115
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Simon G Anderson
14Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK (SA)
15The George Institute for Global Health, University of Oxford, Oxford Martin School, 34 Broad Street Oxford OX1 3BD, UK (SA)
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Robin Beaumont
4Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom
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David A Bechtold
16Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
17Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK
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Brian Cade
10Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital
11Division of Sleep Medicine, Harvard Medical School, University of Bristol, UK
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Sek Kathiresan
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
3Broad Institute, Cambridge, MA, USA
5Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
18Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA
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Max A Little
19Department of Mathematics, Aston University, Birmingham, UK
20Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Annemarie I Luik
21Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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Andrew S Loudon
16Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
17Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK
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Shaun Purcell
22Department of Psychiatry, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115
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Rebecca C Richmond
23School of Social and Community Medicine, University of Bristol, Bristol, UK
24Medical Research Council Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, BS8 2BN UK
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Frank AJL Scheer
10Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital
11Division of Sleep Medicine, Harvard Medical School, University of Bristol, UK
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Jessica Tyrrell
4Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom
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John Winkelman
25Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, MA, USA
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Linn B Strand
7K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Norway
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Jonas B. Nielsen
27Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Cristen J. Willer
27Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
28Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
29Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
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Susan Redline
30Departments of Medicine, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
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Kai Spiegelhalder
31Clinic for Psychiatry and Psychotherapy, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
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Simon D Kyle
21Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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David W Ray
16Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
17Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK
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John-Anker Zwart
7K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Norway
26FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway
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Kristian Hveem
7K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Norway
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Timothy M Frayling
4Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom
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Deborah Lawlor
8MRC Integrative Epidemiology Unit at the University of Bristol, UK
12Population Health Sciences, Bristol Medical School, University of Bristol, UK
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Martin K Rutter
16Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
17Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK
32Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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Michael N Weedon
4Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom
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Richa Saxena
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
3Broad Institute, Cambridge, MA, USA
30Departments of Medicine, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston
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ABSTRACT

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships 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, phototransduction and muscle development pathways 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 heart disease, depressive symptoms and subjective well-being.

One Sentence Summary We identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.

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Posted February 02, 2018.
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Biological and clinical insights from genetics of insomnia symptoms
Jacqueline M Lane, Samuel Jones, Hassan S Dashti, Andrew R Wood, Krishna Aragam, Vincent T. van Hees, Ben Brumpton, Bendik Winsvold, Heming Wang, Jack Bowden, Yanwei Song, Krunal Patel, Simon G Anderson, Robin Beaumont, David A Bechtold, Brian Cade, Sek Kathiresan, Max A Little, Annemarie I Luik, Andrew S Loudon, Shaun Purcell, Rebecca C Richmond, Frank AJL Scheer, Jessica Tyrrell, John Winkelman, HUNT All In Sleep, Linn B Strand, Jonas B. Nielsen, Cristen J. Willer, Susan Redline, Kai Spiegelhalder, Simon D Kyle, David W Ray, John-Anker Zwart, Kristian Hveem, Timothy M Frayling, Deborah Lawlor, Martin K Rutter, Michael N Weedon, Richa Saxena
bioRxiv 257956; doi: https://doi.org/10.1101/257956
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Biological and clinical insights from genetics of insomnia symptoms
Jacqueline M Lane, Samuel Jones, Hassan S Dashti, Andrew R Wood, Krishna Aragam, Vincent T. van Hees, Ben Brumpton, Bendik Winsvold, Heming Wang, Jack Bowden, Yanwei Song, Krunal Patel, Simon G Anderson, Robin Beaumont, David A Bechtold, Brian Cade, Sek Kathiresan, Max A Little, Annemarie I Luik, Andrew S Loudon, Shaun Purcell, Rebecca C Richmond, Frank AJL Scheer, Jessica Tyrrell, John Winkelman, HUNT All In Sleep, Linn B Strand, Jonas B. Nielsen, Cristen J. Willer, Susan Redline, Kai Spiegelhalder, Simon D Kyle, David W Ray, John-Anker Zwart, Kristian Hveem, Timothy M Frayling, Deborah Lawlor, Martin K Rutter, Michael N Weedon, Richa Saxena
bioRxiv 257956; doi: https://doi.org/10.1101/257956

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