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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


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.

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 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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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





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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Peer review information Nature Neuroscience thanks Gerome Breen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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 (2021).

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