Letter | Published:

Biological and clinical insights from genetics of insomnia symptoms

Nature Geneticsvolume 51pages387393 (2019) | Download Citation

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 identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 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 glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.

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Data availability

GWAS summary statistics are available at the Sleep Disorders Knowledge Portal data download page (http://sleepdisordergenetics.org/informational/data/).

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Acknowledgements

This research was conducted by using the UK Biobank Resource (UK Biobank applications 6818 and 9072). We would like to thank the participants and researchers from the UK Biobank who contributed or collected data. This work was supported by NIH grants R01DK107859 (R.S.), R21HL121728 (R.S.), F32DK102323 (J.M.L.), R01HL113338 (J.M.L., S.R., and R.S.), R01DK102696 (R.S. and F.S.), NHLBI R35 35HL135818 (S.R. and R.S), R01DK105072 (R.S. and F.S.), T32HL007567 (J.M.L.), K01HL136884 (J.M.L.), and HG003054 (H.W.), The MGH Research Scholar Fund (R.S.), The University of Manchester (Research Infrastructure Fund), the Wellcome Trust (salary support for D.W.R. and A.S.L.), UK Medical Research Council MC_UU_12013/5 (D.A.L.), UK Medical Research Council MC_UU_00011/6 (D.A.L.), and UK National Institute of Health Research NF-SI-0611-10196 (D.A.L.). A.R.W. and T.M.F. are supported by a European Research Council grant (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). S.E.J. is funded by the Medical Research Council (MR/M005070/1). M.N.W. is supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF). The following groups provided summary statistics to LDHub and MR-base: ADIPOGen (Adiponectin Genetics Consortium), C4D (Coronary Artery Disease Genetics Consortium), CARDIoGRAM (Coronary Artery Disease Genome-wide Replication and Meta-analysis), CKDGen (Chronic Kidney Disease Genetics Consortium), dbGAP (Database of Genotypes and Phenotypes), DIAGRAM (Diabetes Genetics Replication and Meta-analysis), ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis), EAGLE (Early Genetics & Lifecourse Epidemiology Eczema Consortium, excluding 23andMe), EGG (Early Growth Genetics Consortium), GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European community), GCAN (Genetic Consortium for Anorexia Nervosa), GEFOS (Genetic Factors for Osteoporosis Consortium), GIANT (Genetic Investigation of Anthropometric Traits), GIS (Genetics of Iron Status Consortium), GLGC (Global Lipids Genetics Consortium), GPC (Genetics of Personality Consortium), GUGC (Global Urate and Gout Consortium), HaemGen (Haemotological and Platelet Traits Genetics Consortium), HRgene (Heart Rate Consortium), IIBDGC (International Inflammatory Bowel Disease Genetics Consortium), ILCCO (International Lung Cancer Consortium), IMSGC (International Multiple Sclerosis Genetic Consortium), MAGIC (Meta-analyses of Glucose and Insulin-related Traits Consortium), MESA (Multi-ethnic Study of Atherosclerosis), PGC (Psychiatric Genomics Consortium), Project MinE consortium, ReproGen (Reproductive Genetics Consortium), SSGAC (Social Science Genetics Association Consortium), TAG (Tobacco and Genetics Consortium), TRICL (Transdisciplinary Research in Cancer of the Lung Consortium), and UK Biobank. The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration among the HUNT Research Centre (Faculty of Medicine, NTNU, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and Norwegian Institute of Public Health. We are grateful for the contributions from H. Zhang and H. M. Kang. We also acknowledge the support given to us by the Genotyping core and J. Chen. The K.G. Jebsen center for genetic epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), and the Central Norway Regional Health Authority. B.B. and L.B.S. received research grants from The Liaison Committee for education, research and innovation in central Norway. We thank the International EU-RLS-GENE Consortium and KORA for providing RLS GWAS data.

Author information

Author notes

  1. These authors contributed equally: Jacqueline M. Lane, Samuel E. Jones.

  2. These authors jointly supervised this work: Deborah A. Lawlor, Martin K. Rutter, Michael N. Weedon, Richa Saxena.

  3. A list of members and affiliations appears at the end of the paper

Affiliations

  1. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Jacqueline M. Lane
    • , Hassan S. Dashti
    • , Krishna G. Aragam
    • , Yanwei Song
    • , Krunal Patel
    • , Mary Haas
    • , Sekar Kathiresan
    •  & Richa Saxena
  2. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Jacqueline M. Lane
    •  & Richa Saxena
  3. Broad Institute, Cambridge, MA, USA

    • Jacqueline M. Lane
    • , Hassan S. Dashti
    • , Krishna G. Aragam
    • , Heming Wang
    • , Yanwei Song
    • , Brian E. Cade
    • , Mary Haas
    • , Sekar Kathiresan
    • , Frank A. J. L. Scheer
    •  & Richa Saxena
  4. Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK

    • Samuel E. Jones
    • , Andrew R. Wood
    • , Robin N. Beaumont
    • , Jessica Tyrrell
    • , Timothy M. Frayling
    •  & Michael N. Weedon
  5. Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Krishna G. Aragam
    •  & Sekar Kathiresan
  6. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    • Krishna G. Aragam
    •  & Sekar Kathiresan
  7. Netherlands eScience Center, Amsterdam, the Netherlands

    • Vincent T. van Hees
    • , Anne H. Skogholt
    • , Ben Brumpton
    • , Bendik S. Winsvold
    • , John-Anker Zwart
    • , Kristian Hveem
    • , Linn B. Strand
    •  & Maiken E. Gabrielsen
  8. K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway

    • Linn B. Strand
    • , Bendik S. Winsvold
    • , Ben Brumpton
    • , Kristian Hveem
    • , John-Anker Zwart
    •  & Ben Brumpton
  9. FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway

    • Bendik S. Winsvold
    • , Ben Brumpton
    •  & Jonas B. Nielsen
  10. Division of Clinical Neuroscience, Oslo University Hospital and University of Oslo, Oslo, Norway

    • Bendik S. Winsvold
    •  & John-Anker Zwart
  11. Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    • Heming Wang
    • , Brian E. Cade
    •  & Frank A. J. L. Scheer
  12. Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Heming Wang
    • , Brian E. Cade
    •  & Frank A. J. L. Scheer
  13. MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK

    • Jack Bowden
    • , Ben Brumpton
    •  & Deborah A. Lawlor
  14. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

    • Jack Bowden
    •  & Deborah A. Lawlor
  15. College of Science, Northeastern University, Boston, MA, USA

    • Yanwei Song
    •  & Krunal Patel
  16. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    • Simon G. Anderson
  17. Farr Institute of Health Informatics Research, University College London, London, UK

    • Simon G. Anderson
  18. Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    • David A. Bechtold
    • , Andrew S. Loudon
    • , David W. Ray
    •  & Martin K. Rutter
  19. Department of Mathematics, Aston University, Birmingham, UK

    • Max A. Little
  20. Media Lab, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Max A. Little
  21. Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    • Annemarie I. Luik
    •  & Simon D. Kyle
  22. Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands

    • Annemarie I. Luik
  23. Department of Psychiatry, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • Shaun Purcell
  24. School of Social and Community Medicine, University of Bristol, Bristol, UK

    • Rebecca C. Richmond
  25. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • Rebecca C. Richmond
  26. Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    • Barbara Schormair
    • , Juliane Winkelmann
    •  & Chen Zhao
  27. Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, MA, USA

    • John W. Winkelman
  28. Cluster for Systems Neurology (SyNergy), Munich, Germany

    • Juliane Winkelmann
  29. Institute of Human Genetics, Technische Universität München, Munich, Germany

    • Juliane Winkelmann
  30. Neurogenetics, Technische Universität München, Munich, Germany

    • Juliane Winkelmann
  31. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    • Cristen J. Willer
    • , Lars Fritsche
    •  & Cristen J. Willer
  32. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    • Cristen J. Willer
    • , Wei Zhou
    •  & Cristen J. Willer
  33. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    • Cristen J. Willer
    •  & Cristen J. Willer
  34. Departments of Medicine, Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    • Susan Redline
  35. Clinic for Psychiatry and Psychotherapy, Medical Centre—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    • Kai Spiegelhalder
  36. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX37LE/NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK

    • David W. Ray
  37. Department of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

    • Bendik S. Winsvold
    • , John-Anker Zwart
    •  & Ben Brumpton
  38. Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    • Martin K. Rutter
  39. FORMI, Oslo University Hospital, Oslo, Norway

    • Amy E. Martinsen
    • , Linda M. Pedersen
    •  & Marie U. Lie
  40. Department of Health Promotion, Norwegian Institute of Public Health, Bergen, Norway

    • Børge Sivertsen
  41. Institute for Mental Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    • Daniela Bragantini
  42. Department of Research and Development, Division of Psychiatry, St. Olavs University Hospital, Trondheim, Norway

    • Håvard Kallestad
    •  & Ismail C. Guzey
  43. Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway

    • Imre Janszky
  44. Oslo University Hospital, Department of Neurology, Oslo, Norway

    • Kristian B. Nilsen
  45. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Marianne B. Johnsen
  46. Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim, Norway

    • Morten Engstrøm
    •  & Trond Sand

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Consortia

  1. HUNT All In Sleep

Contributions

The study was designed by J.M.L., S.E.J., A.R.W., H.S.D., V.T.V.H., K.H., B.B., L.B.S., B.S.W., K.G.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.E.J., A.R.W., H.S.D., V.T.V.H., C.Z., J.B.N., J.-A.Z., M.H., R.N.B., J.T., K.G.A., H.W., Y.S., K.P., S.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.B., L.B.S., H.W., and R.S. wrote the manuscript, and all coauthors 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.

Competing interests

J.W.W. is a consultant for Merck and Flex Pharma. He receives royalties from UpToDate. He has received speaker fees and travel support from Otsuka. He has received research grants from UCB Pharma, NeuroMetrix, NIMH, the RLS Foundation, and Luitpold Pharma. F.A.J.L.S. has received lecture fees from Bayer HealthCare, Sentara HealthCare, Philips, Vanda Pharmaceuticals, and Pfizer. D.A.L. has received funding from Medtronic and Roche Diagnostics for biomarker research unrelated to this study. M.K.R. has acted as a consultant for GlaxoSmithKline, Novo Nordisk, Roche, and Merck Sharp & Dohme (MSD), and also participated in advisory-board meetings on their behalf. M.K.R. has received lecture fees from MSD and grant support from Novo Nordisk, MSD, and GlaxoSmithKline.

Corresponding author

Correspondence to Richa Saxena.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–7 and Supplementary Note

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–20

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Issue Date

DOI

https://doi.org/10.1038/s41588-019-0361-7

Further reading

  • Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour

    • Samuel E. Jones
    • , Vincent T. van Hees
    • , Diego R. Mazzotti
    • , Pedro Marques-Vidal
    • , Séverine Sabia
    • , Ashley van der Spek
    • , Hassan S. Dashti
    • , Jorgen Engmann
    • , Desana Kocevska
    • , Jessica Tyrrell
    • , Robin N. Beaumont
    • , Melvyn Hillsdon
    • , Katherine S. Ruth
    • , Marcus A. Tuke
    • , Hanieh Yaghootkar
    • , Seth A. Sharp
    • , Yingjie Ji
    • , Jamie W. Harrison
    • , Rachel M. Freathy
    • , Anna Murray
    • , Annemarie I. Luik
    • , Najaf Amin
    • , Jacqueline M. Lane
    • , Richa Saxena
    • , Martin K. Rutter
    • , Henning Tiemeier
    • , Zoltán Kutalik
    • , Meena Kumari
    • , Timothy M. Frayling
    • , Michael N. Weedon
    • , Philip R. Gehrman
    •  & Andrew R. Wood

    Nature Communications (2019)