Cross-ancestry genome-wide association study and systems-level integrative analyses implicate new risk genes and therapeutic targets for depression
Open accessPublished version of a preprint
Abstract
Deciphering the genetic architecture of depression is pivotal for characterizing the associated pathophysiological processes and development of new therapeutics. Here we conducted a cross-ancestry genome-wide meta-analysis on depression (416,437 cases and 1,308,758 controls) and identified 287 risk loci, of which 49 are new. Variant-level fine mapping prioritized potential causal variants and functional genomic analysis identified variants that regulate the binding of transcription factors. We validated that 80% of the identified functional variants are regulatory variants, and expression quantitative trait loci analysis uncovered the potential target genes regulated by the prioritized risk variants. Gene-level analysis, including transcriptome and proteome-wide association studies, colocalization and Mendelian randomization-based analyses, prioritized potential causal genes and drug targets. Gene prioritization analyses highlighted likely causal genes, including TMEM106B, CTNND1, AREL1 and so on. Pathway analysis indicated significant enrichment of depression risk genes in synapse-related pathways. Finally, knockdown of Tmem106b in mice resulted in depression-like behaviours, supporting the involvement of Tmem106b in depression. Our study identified new risk loci, likely causal variants and genes for depression, providing important insights into the genetic architecture of depression and potential therapeutic targets.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Giambartolomei, C., Vukcevic, D., Schadt, E. E., Franke, L., Hingorani, A. D., Wallace, C., & Plagnol, V. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004383 · Cited by 4,261 · see citing works
Malhi, G. S., & Mann, J. J. (2018) · The Lancet · doi:10.1016/s0140-6736(18)31948-2 · Cited by 4,099 · see citing works
MAGMA: Generalized Gene-Set Analysis of GWAS Data
de Leeuw, C. A., Mooij, J. M., Heskes, T., & Posthuma, D. (2015) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1004219 · Cited by 3,653 · see citing works
Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0326-7 · Cited by 2,565 · see citing works
Synaptic Dysfunction in Depression: Potential Therapeutic Targets
Duman, R. S., & Aghajanian, G. K. (2012) · Science · doi:10.1126/science.1222939 · Cited by 1,651 · cited 1× · see citing works
“Notably, some previous studies have also suggested that the synapse may have an important role in depression 8,44–48 .”
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder
Gandal, M. J., Zhang, P., Hadjimichael, E., Walker, R. L., Chen, C., Liu, S., Won, H., van Bakel, H., Varghese, M., Wang, Y., et al. (2018) · Science · doi:10.1126/science.aat8127 · Cited by 1,247 · see citing works
Self-citationMajor depressive disorder: hypothesis, mechanism, prevention and treatment
Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., & Li, B. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01738-y · Cited by 1,061 · cited 1× · see citing works
“…mouse orthologue of human TMEM106B , Ensembl ID: ENSMUSG00000029571) in the mouse hippocampus, a brain region that has been previously reported to have a critical role in depression on the basis of mouse models and human studies 32–35 and where Tmem106b is highly expressed 36 (Supplementary Fig.”
Self-citationHyde, C. L., Nagle, M. W., Tian, C., Chen, X., Paciga, S. A., Wendland, J. R., Tung, J. Y., Hinds, D. A., Perlis, R. H., & Winslow, A. R. (2016) · Nature Genetics · doi:10.1038/ng.3623 · Cited by 784 · see citing works
Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model
Price, R. B., & Duman, R. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0615-x · Cited by 721 · see citing works
Fine-mapping from summary data with the “Sum of Single Effects” model
Zou, Y., Carbonetto, P., Wang, G., & Stephens, M. (2022) · PLOS Genetics · doi:10.1371/journal.pgen.1010299 · Cited by 429 · see citing works
Tartt, A. N., Mariani, M. B., Hen, R., Mann, J. J., & Boldrini, M. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01520-y · Cited by 408 · cited 1× · see citing works
“…mouse orthologue of human TMEM106B , Ensembl ID: ENSMUSG00000029571) in the mouse hippocampus, a brain region that has been previously reported to have a critical role in depression on the basis of mouse models and human studies 32–35 and where Tmem106b is highly expressed 36 (Supplementary Fig.”
Hill, M. N., Miller, G. E., Carrier, E. J., Gorzalka, B. B., & Hillard, C. J. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.03.013 · Cited by 328 · see citing works
Wong, M.-L., Dong, C., Maestre-Mesa, J., & Licinio, J. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.59 · Cited by 295 · see citing works
Boucher, A. A., Arnold, J. C., Hunt, G. E., Spiro, A., Spencer, J., Brown, C., McGregor, I. S., Bennett, M. R., & Kassiou, M. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.05.049 · Cited by 108 · see citing works
P2X7 Receptor: A Potential Therapeutic Target for Depression?
Deussing, J. M., & Arzt, E. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.07.005 · Cited by 97 · see citing works
Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder
Team7, T. 2. R., Li, X., Luo, Z., Gu, C., Hall, L. S., McIntosh, A. M., Zeng, Y., Porteous, D. J., Hayward, C., Li, M., et al. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0078-9 · Cited by 41 · see citing works
Flagged first, then by citations
- Authors
- Li, Y., Dang, X., Chen, R., Teng, Z., Wang, J., Li, S., Yue, Y., Mitchell, B. L., Zeng, Y., Yao, Y.-G., Li, M., Liu, Z., Yuan, Y., Li, T., Zhang, Z., & Luo, X.-J.
- Affiliations
- Zhongda Hospital Southeast University (CN)
- Kunming Institute of Zoology (CN)
- Kunming Medical University (CN)
- Zhengzhou University (CN)
- QIMR Berghofer Medical Research Institute (AU)
- Wuhan University (CN)
- Hangzhou Seventh Peoples Hospital (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Yuan, Yonggui
- Li, Tao
- Zhang, Zhijun
- Luo, Xiong-Jian
- ORCID
- Venue
- Nature Human Behaviour
- Published
- 2025-02-24
- Volume
- 9
- Issue
- 4
- Pages
- 806-823
- ISSN
- 2397-3374 (ISSN-L)
- OpenAlex
- W4407884030
- Cited by
- 30
- References
- 17
- Citations by year
- 2026: 17 · 2025: 10 · 2023: 3
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Human Behaviour (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Natural Science Foundation of China (U2102205, 82301690)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- depression, genetic susceptibility loci, regulatory variants, transcription factor binding, expression quantitative trait loci, transcriptome-wide association study, Mendelian randomization, causal gene prioritization, therapeutic target, TMEM106B, p120 catenin, depression-like behavior
- MeSH terms
- Animals, Depression, Humans, Membrane Proteins, Nerve Tissue Proteins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Mice, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
