eprintid: 10206251
rev_number: 9
eprint_status: archive
userid: 699
dir: disk0/10/20/62/51
datestamp: 2025-03-19 12:09:36
lastmod: 2025-03-19 12:09:36
status_changed: 2025-03-19 12:09:36
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Mcintosh, Andrew M
creators_name: Lewis, Cathryn M
title: Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D79
divisions: FH4
keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, GENERALIZED ANXIETY DISORDER, HIPPOCAMPAL NEUROGENESIS, PREGABALIN AUGMENTATION, MAJOR DEPRESSION, GENE-EXPRESSION, ANTIDEPRESSANTS, METAANALYSIS, LOCI, HERITABILITY, REWARD
note: © 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/).
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: 2025-02-06
date_type: published
publisher: CELL PRESS
official_url: https://doi.org/10.1016/j.cell.2024.12.002
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2363086
doi: 10.1016/j.cell.2024.12.002
medium: Print-Electronic
pii: S0092-8674(24)01415-6
lyricists_name: Bass, Nicholas James
lyricists_name: McQuillin, Andrew
lyricists_name: Kuchenbaecker, Karoline
lyricists_name: Lewis, Glyn
lyricists_id: NJBAS95
lyricists_id: AMCQU28
lyricists_id: KBEKK98
lyricists_id: GHLEW69
actors_name: Kuchenbaecker, Karoline
actors_id: KBEKK98
actors_role: owner
funding_acknowledgements: 1IK2BX005058 [Million Veteran Program, Office of Research and Development, Veterans Health Administration]; I01CX001849 [Million Veteran Program, Office of Research and Development, Veterans Health Administration]; MH124873 [US National Institutes of Health]; MH124871 [US National Institutes of Health]; R102-A9118 [Lund-beck Foundation]; R155-2014-1724 [Lund-beck Foundation]; [Stanley Medical Research Institute]; [Novo Nordisk Foundation]; CIDR:NGRC [NINDS]; CA093459 [NINDS]; CA097007 [NINDS]; ES011740 [NINDS]; CA133996 [NINDS]; [NIHR Maudsley Biomedical Research Centre and Maudsley NHS Foundation Trust and King's College London]; 220857/Z/20/Z [Wellcome Trust]; 847776 [European Union]; 948561 [European Union]
full_text_status: public
publication: Cell
volume: 188
number: 3
pagerange: 640-652.e9
pages: 23
event_location: United States
issn: 0092-8674
citation:        Mcintosh, Andrew M;    Lewis, Cathryn M;      (2025)    Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies.                   Cell , 188  (3)   640-652.e9.    10.1016/j.cell.2024.12.002 <https://doi.org/10.1016/j.cell.2024.12.002>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10206251/7/Kuchenbaecker_1-s2.0-S0092867424014156-main.pdf