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Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (Cai, N.)

Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies.

Cell 188, 640-652 (2025)
Publ. Version/Full Text Research data DOI
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Generalized Anxiety Disorder; Hippocampal Neurogenesis; Pregabalin Augmentation; Major Depression; Gene-expression; Antidepressants; Metaanalysis; Loci; Heritability; Reward
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 188, Issue: 3, Pages: 640-652 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Helmholtz Pioneer Campus (HPC)
Institute of Computational Biology (ICB)
Grants NIHR Maudsley Biomedical Research Centre and Maudsley NHS Foundation Trust and King's College London
Novo Nordisk Foundation
Stanley Medical Research Institute