Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies
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Author(s)
Type
Journal Article
Abstract
In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.
Date Issued
2025-02-06
Date Acceptance
2024-12-05
Citation
Cell, 2025, 188 (3), pp.640-652
ISSN
0092-8674
Publisher
Cell Press
Start Page
640
End Page
652
Journal / Book Title
Cell
Volume
188
Issue
3
Copyright Statement
© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39814019
PII: S0092-8674(24)01415-6
Subjects
ANTIDEPRESSANTS
Biochemistry & Molecular Biology
Cell Biology
GENE-EXPRESSION
GENERALIZED ANXIETY DISORDER
HERITABILITY
HIPPOCAMPAL NEUROGENESIS
Life Sciences & Biomedicine
LOCI
MAJOR DEPRESSION
METAANALYSIS
PREGABALIN AUGMENTATION
REWARD
Science & Technology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-01-14