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Brain proteome-wide association study implicates novel proteins in depression pathogenesis

Nature Neuroscience volume 24, pages 810–817 (2021)Cite this article

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Abstract

Depression is a common condition, but current treatments are only effective in a subset of individuals. To identify new treatment targets, we integrated depression genome-wide association study (GWAS) results (N = 500,199) with human brain proteomes (N = 376) to perform a proteome-wide association study of depression followed by Mendelian randomization. We identified 19 genes that were consistent with being causal in depression, acting via their respective cis-regulated brain protein abundance. We replicated nine of these genes using an independent depression GWAS (N = 307,353) and another human brain proteomic dataset (N = 152). Eleven of the 19 genes also had cis-regulated mRNA levels that were associated with depression, based on integration of the depression GWAS with human brain transcriptomes (N = 888). Meta-analysis of the discovery and replication proteome-wide association study analyses identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously implicated in depression by GWAS. Together, these findings provide promising brain protein targets for further mechanistic and therapeutic studies.

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Fig. 1: Discovery PWAS identified 19 genes consistent with being causal in depression.
Fig. 2: PPI network and pathways among the 25 potentially depression-causal proteins identified from the PWAS meta-analysis.
Fig. 3: Single-cell-type expression of the potentially depression-causal genes.

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Data availability

Phenotypic, proteomic and transcriptomic data used in this manuscript are available via the AD Knowledge Portal (https://adknowledgeportal.org). The AD Knowledge Portal is a platform for accessing data, analyses and tools generated by the Accelerating Medicines Partnership (AMP-AD) Target Discovery Program and other National Institute on Aging (NIA)-supported programs to enable open-science practices and accelerate translational learning. The data, analyses and tools are shared early in the research cycle without a publication embargo on secondary use. Data are available for general research use according to the following requirements for data access and data attribution (https://adknowledgeportal.org/DataAccess/Instructions). For access to results of the pQTL analysis, protein weights and transcript weights described in this manuscript, see https://doi.org/10.7303/syn24872746.

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Acknowledgements

We thank the participants of the ROS, MAP, Mayo, Mount Sinai Brain Bank and Banner Sun Health Research Institute Brain and Body Donation Program for their time and participation, and we thank the research participants and employees of 23andMe for making this work possible. The following NIH grants supported this work: P30 AG066511 (A.I.L.), P30 AG10161 (D.A.B.), P30 NS055077 (A.I.L.), P50 AG025688 (A.I.L.), R01 AG015819 (D.A.B.), R01 AG017917 (D.A.B.), R01 AG053960 (N.T.S.), R01 AG056533 (T.S.W., A.P.W.), R01 AG057911 (N.T.S.), R01 AG061800 (N.T.S.), R56 AG060757 (T.S.W.), R56 AG062256 (T.S.W.), RC2 AG036547 (D.A.B.), RF1 AG057470 (T.S.W.), U01 AG046152 (P.L.D.), U01 AG046161 (A.I.L.), U01 AG061356 (P.L.D.), U01 AG061357 (A.I.L.) and U01 MH115484 (A.P.W.). NIH grants include those that supported the Accelerating Medicine Partnership for AD, the NINDS Emory Neuroscience Core and Goizueta Alzheimer’s Disease Research Center (ADRC) at Emory University, the Rush University ADRC and Arizona State University ADRC that made this work possible. The following Veterans Administration grants supported this work: I01 BX003853 (A.P.W.) and IK4 BX005219 (A.P.W.). The Brain and Body Donation Program has been supported by the NIH, the Arizona Department of Health Services, the Arizona Biomedical Research Commission and the Michael J. Fox Foundation for Parkinson’s Research. Additional support includes grants from the Alzheimer’s Association (N.T.S.), Alzheimer’s Research UK (N.T.S.), The Michael J. Fox Foundation for Parkinson’s Research (N.T.S.) and the Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant 11060 (N.T.S.). The views expressed in this work do not necessarily represent the views of the Veterans Administration or the US government.

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Authors and Affiliations

  1. Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

    Thomas S. Wingo, Yue Liu, Ekaterina S. Gerasimov, James J. Lah & Allan I. Levey

  2. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    Thomas S. Wingo & Michael P. Epstein

  3. Sage Bionetworks, Seattle, WA, USA

    Jake Gockley & Benjamin A. Logsdon

  4. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA

    Duc M. Duong, Eric B. Dammer & Nicholas T. Seyfried

  5. Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA

    Adriana Lori, Paul J. Kim & Aliza P. Wingo

  6. McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Kerry J. Ressler

  7. Banner Sun Health Research Institute, Sun City, AZ, USA

    Thomas G. Beach

  8. Banner Alzheimer’s Institute, Arizona State University and University of Arizona, Phoenix, AZ, USA

    Eric M. Reiman

  9. Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA

    Philip L. De Jager

  10. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    David A. Bennett

  11. Division of Mental Health, Atlanta VA Medical Center, Decatur, GA, USA

    Aliza P. Wingo

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Contributions

A.P.W. and T.S.W. conceptualized and designed the study. T.G.B., E.M.R., P.L.D., J.J.L., D.A.B., N.T.S. and A.I.L. acquired the data. T.S.W., Y.L., E.S.G., J.G., B.A.L., D.M.D., E.B.D. and A.P.W. conducted analyses. T.S.W., Y.L., E.S.G., J.G., B.A.L., A.L., P.J.K., K.J.R., M.P.E. and D.A.B. interpreted the data. A.P.W. and T.S.W. wrote the first draft of the manuscript. All authors critically reviewed and revised the manuscript.

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Correspondence to Thomas S. Wingo or Aliza P. Wingo.

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Wingo, T.S., Liu, Y., Gerasimov, E.S. et al. Brain proteome-wide association study implicates novel proteins in depression pathogenesis. Nat Neurosci 24, 810–817 (2021). https://doi.org/10.1038/s41593-021-00832-6

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