Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits

Anke R Hammerschlag, Sven Stringer, Christiaan A de Leeuw, Suzanne Sniekers, Erdogan Taskesen, Kyoko Watanabe, Tessa F Blanken, Kim Dekker, Bart H W Te Lindert, Rick Wassing, Ingileif Jonsdottir, Gudmar Thorleifsson, Hreinn Stefansson, Thorarinn Gislason, Klaus Berger, Barbara Schormair, Juergen Wellmann, Juliane Winkelmann, Kari Stefansson, Konrad OexleEus J W Van Someren, Danielle Posthuma

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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.

Original languageEnglish
Pages (from-to)1584-1592
Number of pages9
JournalNature Genetics
Volume49
Issue number11
Early online date12 Jun 2017
DOIs
Publication statusPublished - 1 Nov 2017

Funding

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.

FundersFunder number
Dutch Brain Foundation
Dutch National Computing and Networking Services
German Migraine & Headache Society
German Restless Legs Patient Organisation
Swiss RLS Patient Association
Pfizer
Merck Sharp and Dohme
Horizon 2020 Framework Programme671084
GlaxoSmithKline Japan
European Research CouncilERC-ADG-2014-671084 INSOMNIA
Vrije Universiteit Amsterdam
Bundesministerium für Bildung und Forschung01ER0816
Nederlandse Organisatie voor Wetenschappelijk Onderzoek480-05-003, 645-000-003, 453-07-001, VICI 453-14-005
Vifor Pharma
Deutsche Migräne- und Kopfschmerzgesellschaft e.V.
Deutsche Restless Legs Vereinigung

    Keywords

    • Adult
    • Alleles
    • Chromosome Mapping
    • Educational Status
    • Female
    • Gene Expression
    • Gene Frequency
    • Gene Regulatory Networks
    • Genetic Loci
    • Genetic Predisposition to Disease
    • Genome, Human
    • Genome-Wide Association Study
    • Homeodomain Proteins
    • Humans
    • Journal Article
    • Male
    • Myeloid Ecotropic Viral Integration Site 1 Protein
    • Neoplasm Proteins
    • Polymorphism, Single Nucleotide
    • Protein Interaction Mapping
    • Quality of Life
    • Restless Legs Syndrome
    • Sex Factors
    • Sleep Initiation and Maintenance Disorders
    • Type D Personality

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