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

TY - JOUR

T1 - Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Electronic address: [email protected]

AU - Mortensen, Preben Bo

AU - Børglum, Anders

AU - Mors, Ole

N1 - Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2025/2/6

Y1 - 2025/2/6

N2 - 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.

AB - 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.

KW - GWAS

KW - depression

KW - drugs

KW - enrichment

KW - genetic

KW - genome-wide association study

KW - neurons

KW - pharmacotherapies

KW - targets

UR - https://www.scopus.com/pages/publications/85216778397

U2 - 10.1016/j.cell.2024.12.002

DO - 10.1016/j.cell.2024.12.002

M3 - Journal article

C2 - 39814019

SN - 0092-8674

VL - 188

SP - 640-652.e9

JO - Cell

JF - Cell

IS - 3

ER -