Abstract

Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.

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Data availability

The data analyzed in the current study were partly provided by the UK Biobank Study (www.ukbiobank.ac.uk), received under UK Biobank application no. 16406. Our policy is to make genome-wide summary statistics (sumstats) publicly available. Sumstats from the GWAS conducted are available for download from the CNCR Complex Trait Genetics lab at https://ctg.cncr.nl/; see also https://ctg.cncr.nl/software/summary_statistics. Note that our freely available meta-analytic sumstats (insomnia and morningness) represent results excluding the 23andMe sample. This is a non-negotiable clause in the 23andMe data transfer agreement, intended to protect the privacy of the 23andMe research participants. To fully recreate our meta-analytic results for insomnia and morningness: (1) obtain insomnia and morningness sumstats from 23andMe; (2) conduct a meta-analysis of our sumstats with the 23andMe sumstats. 23andMe participant data are shared according to community standards that have been developed to protect against breaches of privacy. Currently, these standards allow for the sharing of summary statistics for at most 10,000 SNPs. The full set of summary statistics can be made available to qualified investigators who enter into an agreement with 23andMe that protects participants’ confidentiality. Interested investigators should email dataset-request@23andme.com for more information.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

This work was funded by The Netherlands Organization for Scientific Research (NWO Brain and Cognition 433-09-228, NWO MagW VIDI 452-12-014, NWO VICI 435-13-005 and 453-07-001, and NWO 645-000-003). P.R.J. was funded by the Sophia Foundation for Scientific Research (S14-27), E.J.W.V.S. was funded by the European Research Council (grant no. ERC-ADG-2014-671084 INSOMNIA), and J.B. was funded by the Swiss National Science Foundation (grant no. P2GEP3_165049). N.G.S. was supported by the Wellcome Trust (grant no. 108726/Z/15/Z). J.H.L. was funded by the Swedish Research Council (Vetenskapsrådet, award no. 2014-3863), the Swedish Brain Foundation (Hjärnfonden) and the Wellcome Trust (grant no. 108726/Z/15/Z). Analyses were carried out on the Genetic Cluster Computer, which is financed by the NWO (480-05-003), by the VU University, Amsterdam, and by the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services SurfSARA. This research has been conducted using the UK Biobank Resource (application no. 16406). We thank the UK Biobank and 23andMe research participants and employees for making this work possible.

Author information

Author notes

  1. These authors contributed equally: Eus J.W. Van Someren, Danielle Posthuma

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

Affiliations

  1. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, the Netherlands

    • Philip R. Jansen
    • , Kyoko Watanabe
    • , Sven Stringer
    • , Anke R. Hammerschlag
    • , Christiaan A. de Leeuw
    • , Mats Nagel
    • , Jeanne E. Savage
    • , Sophie van der Sluis
    • , Tinca J. C. Polderman
    •  & Danielle Posthuma
  2. Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands

    • Philip R. Jansen
    • , Henning Tiemeier
    •  & Tonya White
  3. Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    • Nathan Skene
    • , Ana B. Muñoz-Manchado
    •  & Jens Hjerling-Leffler
  4. UCL Institute of Neurology, Queen Square, London, UK

    • Nathan Skene
    •  & Patrick F. Sullivan
  5. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Julien Bryois
  6. Department of Social, Health and Organisational Psychology, Utrecht University, Utrecht, the Netherlands

    • Jeroen S. Benjamins
  7. Department of Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht, the Netherlands

    • Jeroen S. Benjamins
  8. Department of Clinical Genetics, Section of Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands

    • Mats Nagel
    • , Sophie van der Sluis
    •  & Danielle Posthuma
  9. Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands

    • Henning Tiemeier
  10. 23andMe, Inc., Mountain View, CA, USA

    • Michelle Agee
    • , Babak Alipanahi
    • , Adam Auton
    • , Robert K. Bell
    • , Katarzyna Bryc
    • , Sarah L. Elson
    • , Pierre Fontanillas
    • , Nicholas A. Furlotte
    • , David A. Hinds
    • , Karen E. Huber
    • , Aaron Kleinman
    • , Nadia K. Litterman
    • , Jennifer C. McCreight
    • , Matthew H. McIntyre
    • , Joanna L. Mountain
    • , Elizabeth S. Noblin
    • , Carrie A. M. Northover
    • , Steven J. Pitts
    • , J. Fah Sathirapongsasuti
    • , Olga V. Sazonova
    • , Janie F. Shelton
    • , Suyash Shringarpure
    • , Chao Tian
    • , Catherine H. Wilson
    • , Joyce Y. Tung
    • , David A. Hinds
    • , Vladimir Vacic
    •  & Xin Wang
  11. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  12. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  13. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, The Netherlands

    • August B. Smit
  14. Department of Sleep and Cognition, Netherlands Institute for Neuroscience (an institute of the Royal Netherlands Academy of Arts and Sciences), Amsterdam, The Netherlands

    • Eus J. W. Van Someren
  15. Departments of Psychiatry and Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam University Medical Center, Amsterdam, The Netherlands

    • Eus J. W. Van Someren

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Consortia

  1. The 23andMe Research Team

Contributions

D.P. and E.J.W.V.S. conceived the study. D.P. supervised the pre- and post-GWAS analysis pipeline. P.R.J. and K.W. performed the analyses. S.St. performed the quality control on the UKB data and wrote the analysis pipeline. K.W. wrote the online platform (FUMA) that was used for the follow-up analyses. C.d.L. conducted conditional gene-set analyses. J.B., N.S., A.M.M., and J.H.L. contributed single-cell RNA sequencing information. J.Y.T., D.A.H., V.V., X.W., and the 23andMe Research Team contributed and analyzed the 23andMe cohort data. D.P., E.J.W.V.S., and P.R.J. wrote the paper. A.R.H., J.S.B., M.N., J.E.S., P.F.S., S.v.d.S., T.J.C.P. conducted part of the analyses. A.B.S. interpreted the findings in biological context and commented on the manuscript. H.T. and T.W. read the manuscript. All authors discussed the results and approved the final version of the paper.

Competing interests

P.F.S. is a grant recipient and advisor to Lundbeck A/G. D.A.H., J.Y.T., V.V., and X.W. are employees of 23andMe.

Corresponding author

Correspondence to Danielle Posthuma.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Note and Supplementary Figs. 1–9

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–33

  4. Supplementary Dataset 1

    Regional association plots of 202 genome-wide-significant loci in the insomnia meta-analysis in 1,331,010 individuals.

  5. Supplementary Dataset 2

    Chromatin interaction maps based on significant loci in the insomnia meta-analysis in 1,331,010 individuals.

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https://doi.org/10.1038/s41588-018-0333-3