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PreprintCited by 30Genetic Associations and EpidemiologyTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

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Cross-ancestry genome-wide association study and systems-level integrative analyses implicate new risk genes and therapeutic targets for depression

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Li, Yifan, Dang, Xinglun, Chen, Rui, Wang, Junyang, Li, Shiwu, Mitchell, Brittany L., Yao, Yong-Gang, Li, Ming, Li, Tao, Zhang, Zhijun, Luo, Xiong-Jian·2023·Nature Human Behaviour
DOI 10.1101/2023.02.24.23286411

Preprint — published as 10.1038/s41562-024-02073-6 · Paper page

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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 140 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 (eQTL) analysis uncovered the potential target genes regulated by the prioritized risk variants. Gene-level analysis, including transcriptome-wide association study (TWAS), proteome-wide association study (PWAS), colocalization and Mendelian randomization-based analyses, prioritized potential causal genes and drug targets. Combining evidence from different analyses revealed likely causal genes, including TMEM106B, CTNND1, EPHB2, AREL1, CSE1L, RAB27B, SATU1, TMEM258, DCC, etc . Pathway analysis showed significant enrichment of depression risk genes in synapse-related pathways. Finally, we showed that Tmem106b knockdown resulted in depression-like behaviors in mice, supporting 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.

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Metadata

Authors
Li, Y., Dang, X., Chen, R., Wang, J., Li, S., Mitchell, B. L., Yao, Y.-G., Li, M., Li, T., Zhang, Z., & Luo, X.-J.
Affiliations
  • Zhongda Hospital Southeast University (CN)
  • Kunming Institute of Zoology (CN)
  • Zhengzhou University (CN)
  • QIMR Berghofer Medical Research Institute (AU)
  • Hangzhou Seventh Peoples Hospital (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Li, Tao
  • Zhang, Zhijun
  • Luo, Xiong-Jian
ORCID
Venue
Nature Human Behaviour
Publisher
openRxiv
Published
2023-03-01
Volume
9
Issue
4
Pages
806-823
ISSN
2397-3374 (ISSN-L)
DOI
10.1101/2023.02.24.23286411
OpenAlex
W4407884030
Cited by
30
References
1
Citations by year
2026: 17 · 2025: 10 · 2023: 3
FWCI
4.13
Type
journal article
Language
en
Open access
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 (medical) › 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

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