Abstract

Persistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10−8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.

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Acknowledgements

This work was funded by the Netherlands Organization for Scientific Research (NWO Brain & Cognition 433-09-228, NWO VICI 453-14-005 and 453-07-001, 645-000-003) and by the European Research Council (ERC-ADG-2014-671084 INSOMNIA). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO; 480-05-003), by VU University (Amsterdam, the Netherlands) 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 under application number 16406. We thank the participants and researchers who contributed and collected the data. We thank the participants of the Netherlands Sleep Registry for providing extensive phenotypic data. We thank the participants who provided samples and data for the Icelandic study and our valued colleagues who contributed to data collection and the phenotypic characterization of clinical samples, genotyping and analysis of genome sequence data. We also thank the EU-RLS consortium and the Cooperative Research in the Region of Augsburg (KORA) study for providing the RLS summary statistics. KORA was initiated and is financed by the Helmholtz Zentrum München, which is funded by the German Federal Ministry of Education and Research and by the state of Bavaria. The collection of sociodemographic and clinical data in the DHS was supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from Almirall, AstraZeneca, Berlin Chemie, Boehringer, Boots Health Care, GlaxoSmithKline, Janssen Cilag, McNeil Pharma, MSD Sharp & Dohme, and Pfizer to the University of Münster. Blood collection in the DHS was done through funds from the Institute of Epidemiology and Social Medicine at the University of Münster. Genotyping for the Human Omni chip was supported by the German Ministry of Education and Research (BMBF; grant 01ER0816). Researchers interested in using DHS data are required to sign and follow the terms of a cooperation agreement that includes a number of clauses designed to ensure protection of privacy and compliance with relevant laws. The COR study was supported by unrestricted grants to the University of Münster from the German Restless Legs Patient Organisation (RLS Deutsche Restless Legs Vereinigung), the Swiss RLS Patient Association (Schweizerische Restless Legs Selbsthilfegruppe) and a consortium formed by Boeringer Ingelheim Pharma, Mundipharma Research, Neurobiotec, Roche Pharma, UCB (Germany + Switzerland) and Vifor Pharma. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Researchers interested in using COR data are required to sign and follow the terms of a cooperation agreement that includes a number of clauses designed to ensure protection of privacy and compliance with relevant laws. For further information on DHS and COR, contact K.B. (bergerk@uni-muenster.de). Acknowledgments for data contributed by other consortia that were used for secondary analyses are presented in the Supplementary Note.

Author information

Author notes

    • Konrad Oexle
    • , Eus J W Van Someren
    •  & Danielle Posthuma

    These authors contributed equally to this work.

Affiliations

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

    • Anke R Hammerschlag
    • , Sven Stringer
    • , Christiaan A de Leeuw
    • , Suzanne Sniekers
    • , Erdogan Taskesen
    • , Kyoko Watanabe
    •  & Danielle Posthuma
  2. Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

    • Erdogan Taskesen
  3. Department of Sleep and Cognition, Netherlands Institute for Neuroscience (an institute of the Royal Netherlands Academy of Arts and Sciences), Amsterdam, the Netherlands.

    • Tessa F Blanken
    • , Kim Dekker
    • , Bart H W te Lindert
    • , Rick Wassing
    •  & Eus J W Van Someren
  4. Department of Integrative Neurophysiology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

    • Tessa F Blanken
    •  & Eus J W Van Someren
  5. Department of Psychiatry, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

    • Tessa F Blanken
    •  & Eus J W Van Someren
  6. deCODE Genetics, Amgen, Inc., Reykjavík, Iceland.

    • Ingileif Jonsdottir
    • , Gudmar Thorleifsson
    • , Hreinn Stefansson
    •  & Kari Stefansson
  7. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

    • Ingileif Jonsdottir
    • , Thorarinn Gislason
    •  & Kari Stefansson
  8. Department of Respiratory Medicine and Sleep, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.

    • Thorarinn Gislason
  9. Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

    • Klaus Berger
    •  & Juergen Wellmann
  10. Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.

    • Barbara Schormair
    • , Juliane Winkelmann
    •  & Konrad Oexle
  11. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Barbara Schormair
    •  & Juliane Winkelmann
  12. Neurologische Klinik und Poliklinik, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany.

    • Juliane Winkelmann
  13. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Juliane Winkelmann
  14. Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

    • Danielle Posthuma

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Contributions

D.P. and E.J.W.V.S. conceived the study. A.R.H. and D.P. performed the analyses. T.F.B., K.D., B.H.W.t.L, R.W. and E.J.W.V.S. recruited participants from the NSR and collected and analyzed data for phenotypic validation. C.A.d.L., S. Sniekers, K.W. and E.T. performed secondary analyses. S. Stringer prepared the UK Biobank data for analyses and wrote a pipeline to facilitate efficient data processing. G.T. and I.J. performed the deCODE analyses. K.O. performed the COR and DHS analyses. H.S., T.G., K.B., B.S., J. Wellmann, J. Winkelmann, K.S., K.O. and E.J.W.V.S. contributed data analyzed in this study. A.R.H., K.O., E.J.W.V.S. and D.P. wrote the paper. All authors discussed the results and commented on the paper.

Competing interests

I.J., G.T., H.S. and K.S. are affiliated with deCODE Genetics/Amgen, Inc., and declare competing financial interests as employees. The other authors declare no competing financial interests.

Corresponding author

Correspondence to Danielle Posthuma.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–18, Supplementary Tables 1–3, 5, 7, 8, 10–30, 33 and 34, and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 4

    Functional annotations of the SNPs and SNPs in LD that are associated with insomnia complaints.

  2. 2.

    Supplementary Table 6

    Genome-wide gene associations with insomnia complaints.

  3. 3.

    Supplementary Table 9

    Tissue expression of the genes identified by the insomniacomplaints GWAS and GWGAS.

  4. 4.

    Supplementary Table 31

    Pathway analysis of canonical pathways and GO pathways.

  5. 5.

    Supplementary Table 32

    Enrichment analysis of HotNet2 subnetworks.