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Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions

Nature Neuroscience volume 24, pages 954–963 (2021)Cite this article

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Abstract

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

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Fig. 1: Design of the study and circular Manhattan plot.
Fig. 2: Genetic correlation.
Fig. 3: Tissue-based gene association study (TWAS) and fine mapping.
Fig. 4: gSEM.
Fig. 5: Similar ancestry and trans-ancestry replication analyses.

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Data availability

The GWAS summary statistics generated and/or analyzed during this study are available via dbGaP; the dbGaP accession assigned to the Million Veteran Program is phs001672.v1.p.

The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Visit https://research.23andme.com/collaborate/#dataset-access/ for more information and to apply to access the data.

Code availability

No custom code was used in this study. Software and R packages used are discussed in the text.

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Acknowledgements

We acknowledge the participants and investigators of the FinnGen study, 23andMe, the UK Biobank, the PGC and the Million Veteran Program. We would like to thank the research participants and employees of 23andMe for making this work possible. We thank the veterans who participate in the Million Veteran Program. The following members of the 23andMe Research Team contributed to this study: M. Agee, S. Aslibekyan, A. Auton, R. K. Bell, K. Bryc, S. K. Clark, S. L. Elson, K. Fletez-Brant, P. Fontanillas, N. A. Furlotte, P. M. Gandhi, K. Heilbron, B. Hicks, D. A. Hinds, K. E. Huber, E. M. Jewett, Y. Jiang, A. Kleinman, K.-H. Lin, N. K. Litterman, M. K. Luff, J. C. McCreight, M. H. McIntyre, K. F. McManus, J. L. Mountain, S. V. Mozaffari, P. Nandakumar, E. S. Noblin, C. A. M. Northover, J. O’Connell, A. A. Petrakovitz, S. J. Pitts, G. D. Poznik, J. F. Sathirapongsasuti, A. J. Shastri, J. F. Shelton, S. Shringarpure, C. Tian, J. Y. Tung, R. J. Tunney, V. Vacic, X. Wang and A. S. Zare. From the Yale Department of Psychiatry, Division of Human Genetics, we would like to thank and acknowledge the efforts of A. M. Lacobelle, C. Robinson and C. Tyrell. Funding: this work was supported by funding from the Veterans Affairs Office of Research and Development Million Veteran Program grant CX001849-01 (MVP025) and VA Cooperative Studies Program CSP575B. D.F.L. was supported by an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation.

Author information

Author notes

  1. These authors contributed equally: Daniel F. Levey, Murray B. Stein.

Authors and Affiliations

  1. Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Daniel F. Levey, Frank R. Wendt, Gita A. Pathak, Hang Zhou, Yaira Z. Nuñez, Cassie Overstreet, Renato Polimanti & Joel Gelernter

  2. Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA

    Daniel F. Levey, Frank R. Wendt, Gita A. Pathak, Hang Zhou, Yaira Z. Nuñez, Cassie Overstreet, Renato Polimanti & Joel Gelernter

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

    Murray B. Stein

  4. Departments of Psychiatry and Herbert Wertheim School of Public Health, University of California, San Diego, La Jolla, CA, USA

    Murray B. Stein

  5. Cooperative Studies Program (CSP), VA Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT, USA

    Mihaela Aslan, Krishnan Radhakrishnan & John Concato

  6. Department of General Medicine, Yale University School of Medicine, New Haven, CT, USA

    Mihaela Aslan

  7. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA

    Rachel Quaden & Kelly M. Harrington

  8. Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA

    Kelly M. Harrington

  9. College of Medicine, University of Kentucky, Lexington, KY, USA

    Krishnan Radhakrishnan

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

    Gerard Sanacora

  11. National Center for PTSD Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA

    Gerard Sanacora

  12. Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK

    Andrew M. McIntosh

  13. 23andMe, Inc., Sunnyvale, CA, USA

    Jingchunzi Shi & Suyash S. Shringarpure

  14. Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD, USA

    John Concato

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Consortia

23andMe Research Team

  • Jingchunzi Shi
  •  & Suyash S. Shringarpure

the Million Veteran Program

  • Daniel F. Levey
  • , Frank R. Wendt
  • , Gita A. Pathak
  • , Hang Zhou
  • , Mihaela Aslan
  • , Rachel Quaden
  • , Kelly M. Harrington
  • , Yaira Z. Nuñez
  • , Cassie Overstreet
  • , John Concato
  • , Renato Polimanti
  •  & Joel Gelernter

Contributions

J.G. and M.B.S. secured funding for this project. D.F.L., M.B.S. and J.G. had primary responsibility for design of the study. J.G., M.B.S. and J.C. conceived, supervised and managed the study. K.R. and M.A. assisted with study administration. D.F.L., F.R.W., G.A.P., H.Z., J.S., S.S. and R.P. contributed to genetic and bioinformatic analyses. R.P. was the senior statistical geneticist. K.H., R.Q. and D.F.L. contributed to phenotyping and phenomic analyses. The initial manuscript was drafted by D.F.L., M.B.S. and J.G. Manuscript contributions and interpretation of results were provided by D.F.L., M.B.S., F.R.W., G.A.P., K.H., G.S., H.Z., Y.Z.N., C.O., R.P., A.M., J.C. and J.G. The remaining authors contributed to other organizational or data processing components of the study. All authors saw, had the opportunity to comment on, and approved the final draft.

Corresponding authors

Correspondence to Murray B. Stein or Joel Gelernter.

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Competing interests

M.B.S. reports receiving consulting fees in the past 3 years from Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio Biosciences, EmpowerPharm, Engrail Therapeutics, Genentech/Roche, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals and Oxeia Biopharmaceuticals. In the last 12 months, G.S. has provided consulting services to Allergan, Axsome Therapeutics, Biohaven Pharmaceuticals, Boehringer Ingelheim International, Bristol-Myers Squibb, Clexio Biosciences, Epiodyne, Intra-Cellular Therapies, Janssen, Lundbeck, Minerva Pharmaceuticals, Navitor Pharmaceuticals, NeuroRX, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Seelos Pharmaceuticals and Vistagen Therapeutics. G.S. has received funds for contracted research from Janssen Pharmaceuticals, Merck and the Usona Institute. G.S. holds equity in Biohaven Pharmaceuticals and has received royalties from Yale University, paid from patent licenses with Biohaven Pharmaceuticals. J.S. and S.S. are employed by and hold stock or stock options in 23andMe, Inc. J.G. is named as co-inventor on Patent Cooperation Treaty application no. 15/878,640 titled ‘Genotype-guided dosing of opioid agonists’, filed on January 24, 2018. All other authors declare that they have no competing financial interests.

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Supplementary information

Supplementary Information

Supplemental Figs. 1–5 and Supplementary Tables 1–5.

Reporting Summary

Supplementary Data 1

A table of genetic correlations.

Supplementary Data 2

Transcriptome-wide association study, variant prioritization and co-localization analysis.

Supplementary Data 3

Additional detail on the precise data sources used in the analysis in Fig. 4.

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Levey, D.F., Stein, M.B., Wendt, F.R. et al. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat Neurosci 24, 954–963 (2021). https://doi.org/10.1038/s41593-021-00860-2

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