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Loneliness and depression: bidirectional mendelian randomization analyses using data from three large genome-wide association studies

Molecular Psychiatry volume 28, pages 4594–4601 (2023)Cite this article

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Abstract

Major depression (MD) is a serious psychiatric illness afflicting nearly 5% of the world’s population. A large correlational literature suggests that loneliness is a prospective risk factor for MD; correlational assocations of this nature may be confounded for a variety of reasons. This report uses Mendelian Randomization (MR) to examine potentially causal associations between loneliness and MD. We report on analyses using summary statistics from three large genome wide association studies (GWAS). MR analyses were conducted using three independent sources of GWAS summary statistics. In the first set of analyses, we used available summary statistics from an extant GWAS of loneliness to predict MD risk. We used two sources of outcome data: the Psychiatric Genomics Consortium (PGC) meta-analysis of MD (PGC-MD; N = 142,646) and the Million Veteran Program (MVP-MD; N = 250,215). Finally, we reversed analyses using data from the MVP and PGC samples to identify risk variants for MD and used loneliness outcome data from UK Biobank. We find robust evidence for a bidirectional causal relationship between loneliness and MD, including between loneliness, depression cases status, and a continuous measure of depressive symptoms. The estimates remained significant across several sensitivity analyses, including models that account for horizontal pleiotropy. This paper provides the first genetically-informed evidence that reducing loneliness may play a causal role in decreasing risk for depressive illness, and these findings support efforts to reduce loneliness in order to prevent or ameliorate MD. Discussion focuses on the public health significance of these findings, especially in light of the SARS-CoV-2 pandemic.

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Fig. 1: Mendelian randomization estimates for loneliness exposure with major depressive disorder as the outcome.
Fig. 2: Mendelian randomization estimates for major depressive disorder exposure with loneliness as the outcome.

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Data availability

The data used in this study comes from several sources. Genetic summary statistics for the loneliness instrument are available through the UK Biobank and by request to the authors. The PGC MD summary statistic data is publicly available: https://www.med.unc.edu/pgc/download-results/mdd/. The MVP MD summary statistic data is available on dbGaP via Study Accession: phs001672.v6.p1. MR source code is published on the Open Scientific Framework: https://osf.io/sc6we/.

Notes

  1. The Wray et al. GWAS included UKB participants, and therefore the genetic instruments were first identified in a sample that included UKB participants. For the current sensitivity analysis, in an effort to maintain independent samples for the exposure and outcome data, we used the instruments identified by Wray et al. in the PGC-MDD exposure sample that does not include UKB participants.

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Funding

DAS was partialy supported by a grant from the National Institute of Aging (R01AG078361-01). KWC was partially supported by a Kaplen Fellowship on Depression from the Harvard Medical School, a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, and funding from the National Institute of Mental Health (K08MH127413). DFL was supported by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. REW is supported by a postdoctoral fellowship from the South-Eastern Regional Health Authority (2020024).

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Authors and Affiliations

  1. Department of Psychology, University of Arizona, Tucson, AZ, USA

    David A. Sbarra

  2. Department of Epidemiology and Biostatistics, Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA

    Ferris A. Ramadan & Yann C. Klimentidis

  3. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Karmel W. Choi

  4. Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Karmel W. Choi

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

    Karmel W. Choi

  6. Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Jorien L. Treur

  7. VA Connecticut Healthcare System, Psychiatry Service, West Haven, CT, USA

    Daniel F. Levey & Joel Gelernter

  8. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Daniel F. Levey & Joel Gelernter

  9. School of Psychological Science, University of Bristol, Bristol, UK

    Robyn E. Wootton

  10. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    Robyn E. Wootton

  11. Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway

    Robyn E. Wootton

  12. VA San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA

    Murray B. Stein

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

    Murray B. Stein

  14. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  15. Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    Joel Gelernter

  16. BIO5 Institute, University of Arizona, Tucson, AZ, USA

    Yann C. Klimentidis

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  1. David A. Sbarra
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Contributions

DAS and YCK had full access to all the study data and take full responsibility for the integrity and accuracy of the reporting. MBS and JG contributed equally to the report. Concept and design: DAS, FAR, YCK. Acquisition and interpretation of data: DAS, FAR, YCK, KWC, JLT, DFL, MBS, JLT. Drafting the manuscript: DAS, FAR, YCK. Revision of the manuscript: All authors. Statistical analyses: DAS, FAR, YCK. Administrative, technical, or material support: FAR. Approval of final manuscript: All authors.

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Correspondence to David A. Sbarra.

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Competing interests

MBS in the past 3 years has received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech. He has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board for Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Dr. Stein has stock options in Oxeia Biopharmaceuticals and Epivario.

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Sbarra, D.A., Ramadan, F.A., Choi, K.W. et al. Loneliness and depression: bidirectional mendelian randomization analyses using data from three large genome-wide association studies. Mol Psychiatry 28, 4594–4601 (2023). https://doi.org/10.1038/s41380-023-02259-w

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