Meta-Analysis

. 2023 Sep 28;14(1):6059.

doi: 10.1038/s41467-023-41249-y.

Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration

Isabelle Austin-Zimmerman^{1

2}, Daniel F Levey^{3

4}, Olga Giannakopoulou^{1

5}, Joseph D Deak^{3

4}, Marco Galimberti^{3

4}, Keyrun Adhikari^{3

4}, Hang Zhou^{3

4}, Spiros Denaxas⁶, Haritz Irizar^{1

7}, Karoline Kuchenbaecker^{1

5}, Andrew McQuillin¹; Million Veteran Program; John Concato^{8

9}, Daniel J Buysse¹⁰, J Michael Gaziano^{11

12}, Daniel J Gottlieb^{13

14

15}, Renato Polimanti^{3

4}, Murray B Stein^{16

17}, Elvira Bramon^{1

18}, Joel Gelernter^{19

20}

Affiliations

¹ Department of Mental Health Neuroscience, Division of Psychiatry, University College London, London, W1T 7BN, UK.
² Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
³ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁴ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁵ UCL Genetics Institute, Division of Biosciences, University College London, London, WC1E 6BT, UK.
⁶ Health Data Research UK, Institute of Health Informatics, University College London, London, NW1 2DA, UK.
⁷ Department of Genetics & Genomic Sciences and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ School of Medicine, Yale University, New Haven, CT, 06511, USA.
⁹ Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD, USA.
¹⁰ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, 02130, USA.
¹² Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
¹³ VA Boston Healthcare System, 1400 VFW Parkway (111PI), West Roxbury, MA, 02132, USA.
¹⁴ Division of Sleep and Circadian Disorders, Brigham & Women's Hospital, Boston, MA, USA.
¹⁵ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
¹⁶ Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA.
¹⁷ Departments of Psychiatry and Herbert Wertheim School of Public Health, University of California, San Diego, La Jolla, CA, USA.
¹⁸ Institute of Cognitive Neuroscience, University College London, London, UK.
¹⁹ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.
²⁰ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA. joel.gelernter@yale.edu.

PMID: 37770476
PMCID: PMC10539313
DOI: 10.1038/s41467-023-41249-y

Meta-Analysis

Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration

Isabelle Austin-Zimmerman et al. Nat Commun. 2023.

. 2023 Sep 28;14(1):6059.

doi: 10.1038/s41467-023-41249-y.

Authors

Affiliations

¹ Department of Mental Health Neuroscience, Division of Psychiatry, University College London, London, W1T 7BN, UK.
² Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
³ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁴ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁵ UCL Genetics Institute, Division of Biosciences, University College London, London, WC1E 6BT, UK.
⁶ Health Data Research UK, Institute of Health Informatics, University College London, London, NW1 2DA, UK.
⁷ Department of Genetics & Genomic Sciences and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ School of Medicine, Yale University, New Haven, CT, 06511, USA.
⁹ Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD, USA.
¹⁰ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, 02130, USA.
¹² Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
¹³ VA Boston Healthcare System, 1400 VFW Parkway (111PI), West Roxbury, MA, 02132, USA.
¹⁴ Division of Sleep and Circadian Disorders, Brigham & Women's Hospital, Boston, MA, USA.
¹⁵ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
¹⁶ Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA.
¹⁷ Departments of Psychiatry and Herbert Wertheim School of Public Health, University of California, San Diego, La Jolla, CA, USA.
¹⁸ Institute of Cognitive Neuroscience, University College London, London, UK.
¹⁹ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.
²⁰ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA. joel.gelernter@yale.edu.

PMID: 37770476
PMCID: PMC10539313
DOI: 10.1038/s41467-023-41249-y

Abstract

Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We present genome-wide association studies of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration in adults of European (N = 445,966), African (N = 27,785), East Asian (N = 3141), and admixed-American (N = 16,250) ancestry from UK Biobank and the Million Veteran Programme. In a cross-population meta-analysis, we identify 84 independent loci for short sleep and 1 for long sleep. We estimate SNP-based heritability for both sleep traits in each ancestry based on population derived linkage disequilibrium (LD) scores using cov-LDSC. We identify positive genetic correlation between short and long sleep traits (r_g = 0.16 ± 0.04; p = 0.0002), as well as similar patterns of genetic correlation with other psychiatric and cardiometabolic phenotypes. Mendelian randomisation reveals a directional causal relationship between short sleep and depression, and a bidirectional causal relationship between long sleep and depression.

Trial registration: ClinicalTrials.gov NCT02256644.

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Conflict of interest statement

D.J.B. has served as a paid or unpaid consultant to the National Cancer Institute, Pear Therapeutics, Sleep Number, Idorsia, Eisai, and Weight Watchers International. All consulting agreements have been for a total of <$5000 per year from any single entity. D.J.B. is an author of the Pittsburgh Sleep Quality Index, Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A), Brief Pittsburgh Sleep Quality Index (B-PSQI), Daytime Insomnia Symptoms Scale, Pittsburgh Sleep Diary, Insomnia Symptom Questionnaire, and RU_SATED (copyrights held by University of Pittsburgh). These instruments have been licensed to commercial entities for fees. He is also co-author of the Consensus Sleep Diary (copyright held by Ryerson University), which is licensed to commercial entities for a fee. He has received grant support from NIH, PCORI, AHRQ, VA and Sleep Number. D.J.G. reports participation on Scientific Advisory Boards for Signifier Medical Technologies, Inc., Wesper, Inc., and Powell-Mansfield, Inc., outside of the submitted work. R.P. is paid for his editorial work in the journal Complex Psychiatry and received a research grant outside the scope of this study from Alkermes. M.B.S. has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from NIH, the Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. J.G. is paid for editorial work for the journal Complex Psychiatry. The remaining authors declare no competing interests.

Figures

**Fig. 1. Distribution of self-reported sleep duration in UK Biobank and MVP samples.**
Bars highlight the proportion of participants who reported sleeping each hour as a percentage of the total sample. UK Biobank sample represented in light blue, MVP in dark blue.

Fig. 2. A cross-population meta-analysis of UK Biobank and MVP, with loci reaching a nominal threshold of 1 × 10⁻⁵ highlighted in green, and the red line indicating genome-wide significance threshold of 5 × 10⁻⁸.
TOP: short (≤5 h, n = 62,516) versus normal (7–8 h, n = 412,944) sleep duration, with 28 independent genetic-risk loci reaching genome-wide significance. BOTTOM: long (≥10 h, n = 17,682) versus normal sleep duration with one genome-wide significant locus.

**Fig. 3. Gene-based test for short (top) and long (bottom) sleep duration in cross-population meta-analysis of UK Biobank and MVP cohorts.**
Bonferroni-adjusted significance threshold p < 2.7 × 10⁻⁶ shown as the red line.

**Fig. 4. Cross-population replication analyses.**
Scatter plot for the z-score effect sizes (error band representing 95% confidence intervals) for 46 genome-wide significant loci from the EUR meta-analysis on short sleep on the y-axis against the z-score effect sizes for the same loci in A EAS-only meta-analysis (ρ = 0.290), B AFR-only meta-analysis (ρ = 0.293), and C AMR-only meta-analysis (ρ = 0.398).

**Fig. 5. Summary of significant genetic correlations.**
Genetic correlations performed between short (light blue) and long (dark blue) sleep duration and previously published GWAS results (EUR only). Data presented as r_g (genetic correlation) estimates and standard error. Significance determined following Bonferroni correction for 40 tests; p < 1.25 × 10⁻³.

**Fig. 6. Effect estimates for the bi-directional Mendelian randomisation analyses between short and long sleep and MDD.**
The forest plots show the beta coefficient and 95% confidence intervals for the association between exposures and outcomes using different MR methods.

See this image and copyright information in PMC

References

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Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration

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Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration

Authors

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