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Genome-wide analysis of insomnia disorder

Molecular Psychiatry volume 23, pages 2238–2250 (2018)Cite this article

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Abstract

Insomnia is a worldwide problem with substantial deleterious health effects. Twin studies have shown a heritable basis for various sleep-related traits, including insomnia, but robust genetic risk variants have just recently begun to be identified. We conducted genome-wide association studies (GWAS) of soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). GWAS were carried out separately for each ancestral group (EUR, AFR, LAT) using logistic regression for each of the STARRS component studies (including 3,237 cases and 14,414 controls), and then meta-analysis was conducted across studies and ancestral groups. Heritability (SNP-based) for lifetime insomnia disorder was significant (h2g = 0.115, p = 1.78 × 10−4 in EUR). A meta-analysis including three ancestral groups and three study cohorts revealed a genome-wide significant locus on Chr 7 (q11.22) (top SNP rs186736700, OR = 0.607, p = 4.88 × 10−9) and a genome-wide significant gene-based association (p = 7.61 × 10−7) in EUR for RFX3 on Chr 9. Polygenic risk for sleeplessness/insomnia severity in UK Biobank was significantly positively associated with likelihood of insomnia disorder in STARRS. Genetic contributions to insomnia disorder in STARRS were significantly positively correlated with major depressive disorder (rg = 0.44, se = 0.22, p = 0.047) and type 2 diabetes (rg = 0.43, se = 0.20, p = 0.037), and negatively with morningness chronotype (rg = −0.34, se = 0.17, p = 0.039) and subjective well being (rg = -0.59, se = 0.23, p = 0.009) in external datasets. Insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease.

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Acknowledgements

Funding

Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 (2009-2015) with the National Institutes of Health, National Institute of Mental Health (NIH/NIMH). Subsequently, STARRS-LS was sponsored and funded by the Department of Defense (USUHS grant number HU0001-15-2-0004). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the Department of Defense. Access to Data and Data Analysis: Murray B. Stein MD, MPH 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. Drs. Stein, Chen, Jain, McCarthy, and Ripke, as well as Ms. He and Ms. Sun, conducted and are jointly responsible for the data analysis. The Army STARRS Team consists of: Co-Principal Investigators: Robert J. Ursano, MD (Uniformed Services University of the Health Sciences) and Murray B. Stein, MD, MPH (University of California San Diego and VA San Diego Healthcare System). Site Principal Investigators: Steven Heeringa, PhD (University of Michigan), James Wagner, PhD (University of Michigan) and Ronald C. Kessler, PhD (Harvard Medical School). Army liaison/consultant: Kenneth Cox, MD, MPH (USAPHC (Provisional)). Other team members: Pablo A. Aliaga, MS (Uniformed Services University of the Health Sciences); COL David M. Benedek, MD (Uniformed Services University of the Health Sciences); Susan Borja, PhD (NIMH); Tianxi Cai, ScD (Harvard School of Public Health); Laura Campbell-Sills, PhD (University of California San Diego); Carol S. Fullerton, PhD (Uniformed Services University of the Health Sciences); Nancy Gebler, MA (University of Michigan); Robert K. Gifford, PhD (Uniformed Services University of the Health Sciences); Paul E. Hurwitz, MPH (Uniformed Services University of the Health Sciences); Kevin Jensen, PhD (Yale University); Kristen Jepsen, PhD (University of California San Diego); Tzu-Cheg Kao, PhD (Uniformed Services University of the Health Sciences); Lisa Lewandowski-Romps, PhD (University of Michigan); Holly Herberman Mash, PhD (Uniformed Services University of the Health Sciences); James E. McCarroll, PhD, MPH (Uniformed Services University of the Health Sciences); Colter Mitchell, PhD (University of Michigan); James A. Naifeh, PhD (Uniformed Services University of the Health Sciences); Tsz Hin Hinz Ng, MPH (Uniformed Services University of the Health Sciences); Caroline Nievergelt, PhD (University of California San Diego); Nancy A. Sampson, BA (Harvard Medical School); CDR Patcho Santiago, MD, MPH (Uniformed Services University of the Health Sciences); Ronen Segman, MD (Hadassah University Hospital, Israel); Alan M. Zaslavsky, PhD (Harvard Medical School); and Lei Zhang, MD (Uniformed Services University of the Health Sciences).

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Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein & Michael J. McCarthy

  2. Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein, Sonia Jain, Feng He & Xiaoying Sun

  3. VA San Diego Healthcare System, San Diego, CA, USA

    Murray B. Stein & Michael J. McCarthy

  4. Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA

    Chia-Yen Chen & Jordan W. Smoller

  5. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Chia-Yen Chen, Stephan Ripke & Jordan W. Smoller

  6. Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Chia-Yen Chen & Jordan W. Smoller

  7. Department of Psychiatry, Yale University, New Haven, CT, USA

    Joel Gelernter

  8. VA Connecticut Healthcare System, West Haven, CT, USA

    Joel Gelernter

  9. Departments of Genetics and Neurobiology, Yale University, New Haven, CT, USA

    Joel Gelernter

  10. Institute for Social Research, University of Michigan, Ann Arbor, MI, USA

    Steven G. Heeringa

  11. Department of Health Care Policy, Harvard Medical School, Boston, MA, USA

    Ronald C. Kessler

  12. Department of Psychology, Harvard University, Cambridge, MA, USA

    Matthew K. Nock

  13. Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Gary H. Wynn & Robert J. Ursano

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Correspondence to Murray B. Stein.

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Conflict of interest

Dr. M.B.S. has in the past three years been a consultant for Actelion, Aptinyx, Dart Neuroscience, Healthcare Management Technologies, Janssen, Neurocrine Biosciences, Oxeia Biopharmaceuticals, Pfizer, and Resilience Therapeutics. Dr. M.B.S. owns founders shares and stock options in Resilience Therapeutics and has stock options in Oxeia Biopharmaceticals. Dr. J.W.S. is an unpaid member of the Scientific Advisory Board of PsyBrain, Inc. In the past 3 years, Dr. R.C.K. has been a consultant for Hoffman-La Roche, Inc., Johnson & Johnson Wellness and Prevention, and Sanofi-Aventis Groupe. Dr. R.C.K. has served on advisory boards for Mensante Corporation, Plus One Health Management, Lake Nona Institute, and US Preventive Medicine. Dr. R.C.K. owns 25% share in DataStat, Inc. The remaining authors declare that they have no conflict of interest.

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Stein, M.B., McCarthy, M.J., Chen, CY. et al. Genome-wide analysis of insomnia disorder. Mol Psychiatry 23, 2238–2250 (2018). https://doi.org/10.1038/s41380-018-0033-5

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