Genome-wide analysis of insomnia disorder

Murray B Stein^{1

2

3}, Michael J McCarthy^{4

5}, Chia-Yen Chen^{6

7

8}, Sonia Jain⁹, Joel Gelernter^{10

11

12}, Feng He⁹, Steven G Heeringa¹³, Ronald C Kessler¹⁴, Matthew K Nock¹⁵, Stephan Ripke⁷, Xiaoying Sun⁹, Gary H Wynn¹⁶, Jordan W Smoller^{6

7

8}, Robert J Ursano¹⁶

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. mstein@ucsd.edu.
² Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA. mstein@ucsd.edu.
³ VA San Diego Healthcare System, San Diego, CA, USA. mstein@ucsd.edu.
⁴ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁵ VA San Diego Healthcare System, San Diego, CA, USA.
⁶ Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰ Department of Psychiatry, Yale University, New Haven, CT, USA.
¹¹ VA Connecticut Healthcare System, West Haven, CT, USA.
¹² Departments of Genetics and Neurobiology, Yale University, New Haven, CT, USA.
¹³ Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Psychology, Harvard University, Cambridge, MA, USA.
¹⁶ Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

PMID: 29520036
PMCID: PMC6129221
DOI: 10.1038/s41380-018-0033-5

Genome-wide analysis of insomnia disorder

Murray B Stein et al. Mol Psychiatry. 2018 Nov.

. 2018 Nov;23(11):2238-2250.

doi: 10.1038/s41380-018-0033-5. Epub 2018 Mar 8.

Authors

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. mstein@ucsd.edu.
² Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA. mstein@ucsd.edu.
³ VA San Diego Healthcare System, San Diego, CA, USA. mstein@ucsd.edu.
⁴ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁵ VA San Diego Healthcare System, San Diego, CA, USA.
⁶ Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰ Department of Psychiatry, Yale University, New Haven, CT, USA.
¹¹ VA Connecticut Healthcare System, West Haven, CT, USA.
¹² Departments of Genetics and Neurobiology, Yale University, New Haven, CT, USA.
¹³ Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Psychology, Harvard University, Cambridge, MA, USA.
¹⁶ Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

PMID: 29520036
PMCID: PMC6129221
DOI: 10.1038/s41380-018-0033-5

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 (h²_g = 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 (r_g = 0.44, se = 0.22, p = 0.047) and type 2 diabetes (r_g = 0.43, se = 0.20, p = 0.037), and negatively with morningness chronotype (r_g = -0.34, se = 0.17, p = 0.039) and subjective well being (r_g = -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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Conflict of interest statement

CONFLICT OF INTEREST

Dr. Stein 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. Stein owns founders shares and stock options in Resilience Therapeutics and has stock options in Oxeia Biopharmaceticals. Dr. Smoller is an unpaid member of the Scientific Advisory Board of PsyBrain, Inc. In the past three years, Dr. Kessler has been a consultant for Hoffman-La Roche, Inc., Johnson & Johnson Wellness and Prevention, and Sanofi-Aventis Groupe. Dr. Kessler has served on advisory boards for Mensante Corporation, Plus One Health Management, Lake Nona Institute, and U.S. Preventive Medicine. Dr. Kessler owns 25% share in DataStat, Inc. The remaining authors report nothing to disclose.

Figures

**Figure 1**
Manhattan plot (and Q-Q plot, inset) of NSS1, NSS2, and PPDS trans-ethnic meta-analysis genome-wide association study (GWAS)

**Figure 2**
Locus-zoom plot showing region on Chr 7 containing the genome-wide significant markers in the NSS1, NSS2, and PPDS trans-ethnic meta-analysis

**Figure 3**
Manhattan plot (and Q-Q plot, inset) of NSS1, NSS2, and PPDS combined dataset genome-wide gene-association study (GWGAS)

See this image and copyright information in PMC

References

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Genome-wide analysis of insomnia disorder

Affiliations

Genome-wide analysis of insomnia disorder

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials