Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies
Journal
Cell
Journal Volume
188
Journal Issue
3
Start Page
640-652.e9
ISSN
0092-8674
Date Issued
2025-02
Author(s)
Mark J. Adams
Fabian Streit
Xiangrui Meng
Swapnil Awasthi
Brett N. Adey
Karmel W. Choi
V. Kartik Chundru
Jonathan R.I. Coleman
Bart Ferwerda
Jerome C. Foo
Zachary F. Gerring
Olga Giannakopoulou
Priya Gupta
Alisha S.M. Hall
Arvid Harder
David M. Howard
Christopher Hübel
Alex S.F. Kwong
Daniel F. Levey
Brittany L. Mitchell
Guiyan Ni
Vanessa K. Ota
Oliver Pain
Gita A. Pathak
Eva C. Schulte
Xueyi Shen
Jackson G. Thorp
Alicia Walker
Shuyang Yao
Jian Zeng
Johan Zvrskovec
Dag Aarsland
Ky'Era V. Actkins
Mazda Adli
Esben Agerbo
Mareike Aichholzer
Allison Aiello
Tracy M. Air
Thomas D. Als
Evelyn Andersson
Till F.M. Andlauer
Volker Arolt
Helga Ask
Julia Bäckman
Sunita Badola
Clive Ballard
Karina Banasik
Nicholas J. Bass
Aartjan T.F. Beekman
Sintia Belangero
Tim B. Bigdeli
Elisabeth B. Binder
Ottar Bjerkeset
Gyda Bjornsdottir
Sigrid Børte
Emma Bränn
Alice Braun
Thorsten Brodersen
Tanja M. Brückl
Søren Brunak
Mie T. Bruun
Margit Burmeister
Pichit Buspavanich
Jonas Bybjerg-Grauholm
Enda M. Byrne
Jianwen Cai
Archie Campbell
Megan L. Campbell
Adrian I. Campos
Enrique Castelao
Jorge Cervilla
Boris Chaumette
Chia-Yen Chen
Zhengming Chen
Sven Cichon
Lucía Colodro-Conde
Anne Corbett
Elizabeth C. Corfield
Baptiste Couvy-Duchesne
Nick Craddock
Udo Dannlowski
Gail Davies
E.J.C. de Geus
Ian J. Deary
Franziska Degenhardt
Abbas Dehghan
J. Raymond DePaulo
Michael Deuschle
Maria Didriksen
Khoa Manh Dinh
Nese Direk
Srdjan Djurovic
Anna R. Docherty
Katharina Domschke
Joseph Dowsett
Ole Kristian Drange
Erin C. Dunn
William Eaton
Gudmundur Einarsson
Thalia C. Eley
Samar S.M. Elsheikh
Jan Engelmann
Michael E. Benros
Christian Erikstrup
Valentina Escott-Price
Chiara Fabbri
Yu Fang
Sarah Finer
Josef Frank
Robert C. Free
Linda Gallo
He Gao
Michael Gill
Maria Gilles
Fernando S. Goes
Scott Douglas Gordon
Jakob Grove
Daniel F. Gudbjartsson
Blanca Gutierrez
Tim Hahn
Lynsey S. Hall
Thomas F. Hansen
Magnus Haraldsson
Catharina A. Hartman
Alexandra Havdahl
Caroline Hayward
Stefanie Heilmann-Heimbach
Stefan Herms
Ian B. Hickie
Henrik Hjalgrim
Jens Hjerling-Leffler
Per Hoffmann
Georg Homuth
Carsten Horn
Jouke-Jan Hottenga
David M. Hougaard
Iiris Hovatta
Qin Qin Huang
Donald Hucks
Floris Huider
Karen A. Hunt
Nicholas S. Ialongo
Marcus Ising
Erkki Isometsä
Rick Jansen
Yunxuan Jiang
Ian Jones
Lisa A. Jones
Lina Jonsson
Masahiro Kanai
Robert Karlsson
Siegfried Kasper
Kenneth S. Kendler
Ronald C. Kessler
Stefan Kloiber
James A. Knowles
Nastassja Koen
Julia Kraft
Henry R. Kranzler
Kristi Krebs
Theodora Kunovac Kallak
Zoltán Kutalik
Elisa Lahtela
Marilyn Lake
Margit Hørup Larsen
Eric J. Lenze
Melissa Lewins
Glyn Lewis
Liming Li
Bochao Danae Lin
Kuang Lin
Penelope A. Lind
Yu-Li Liu
Donald J. MacIntyre
Dean F. MacKinnon
Brion S. Maher
Wolfgang Maier
Victoria S. Marshe
Gabriela A. Martinez-Levy
Koichi Matsuda
Hamdi Mbarek
Peter McGuffin
Sarah E. Medland
Susanne Meinert
Christina Mikkelsen
Susan Mikkelsen
Yuri Milaneschi
Iona Y. Millwood
Esther Molina
Francis M. Mondimore
Preben Bo Mortensen
Benoit H. Mulsant
Joonas Naamanka
Jake M. Najman
Matthias Nauck
Igor Nenadić
Kasper R. Nielsen
Ilja M. Nolt
Merete Nordentoft
Markus M. Nöthen
Mette Nyegaard
Michael C. O'Donovan
Asmundur Oddsson
Adrielle M. Oliveira
Catherine M. Olsen
Hogni Oskarsson
Sisse Rye Ostrowski
Michael J. Owen
Richard Packer
Teemu Palviainen
Pedro M. Pan
Carlos N. Pato
Michele T. Pato
Nancy L. Pedersen
Ole Birger Pedersen
Wouter J. Peyrot
James B. Potash
Martin Preisig
Michael H. Preuss
Jorge A. Quiroz
Miguel E. Renteria
Charles F. Reynolds III
John P. Rice
Saori Sakaue
Marcos L. Santoro
Robert A. Schoevers
Andrew Schork
Thomas G. Schulze
Tabea S. Send
Jianxin Shi
Engilbert Sigurdsson
Kritika Singh
Grant C.B. Sinnamon
Lea Sirignano
Olav B. Smeland
Daniel J. Smith
Tamar Sofer
Erik Sørensen
Sundararajan Srinivasan
Hreinn Stefansson
Kari Stefansson
Peter Straub
Mei-Hsin Su
André Tadic
Henning Teismann
Alexander Teumer
Anita Thapar
Pippa A. Thomson
Lise Wegner Thørner
Apostolia Topaloudi
Shih-Jen Tsai
Ioanna Tzoulaki
George Uhl
André G. Uitterlinden
Henrik Ullum
Daniel Umbricht
Robert J. Ursano
Sandra Van der Auwera
Albert M. van Hemert
Abirami Veluchamy
Alexander Viktorin
Henry Völzke
G. Bragi Walters
Xiaotong Wang
Agaz Wani
Myrna M. Weissman
Jürgen Wellmann
David C. Whiteman
Derek Wildman
Gonneke Willemsen
Alexander T. Williams
Bendik S. Winsvold
Stephanie H. Witt
Ying Xiong
Lea Zillich
John-Anker Zwart
Ole A. Andreassen
Bernhard T. Baune
Klaus Berger
Dorret I. Boomsma
Anders D. Børglum
Gerome Breen
Na Cai
Hilary Coon
William E. Copeland
Byron Creese
Carlos S. Cruz-Fuentes
Darina Czamara
Lea K. Davis
Eske M. Derks
Enrico Domenici
Paul Elliott
Andreas J. Forstner
Micha Gawlik
Joel Gelernter
Hans J. Grabe
Steven P. Hamilton
Kristian Hveem
Catherine John
Jaakko Kaprio
Tilo Kircher
Marie-Odile Krebs
Mikael Landén
Kelli Lehto
Douglas F. Levinson
Qingqin S. Li
Klaus Lieb
Ruth J.F. Loos
Yi Lu
Susanne Lucae
Jurjen J. Luykx
Hermine H.M. Maes
Patrik K. Magnusson
Hilary C. Martin
Nicholas G. Martin
Andrew McQuillin
Christel M. Middeldorp
Lili Milani
Ole Mors
Daniel J. Müller
Bertram Müller-Myhsok
Yukinori Okada
Albertine J. Oldehinkel
Sara A. Paciga
Colin N.A. Palmer
Peristera Paschou
Brenda W.J.H. Penninx
Roy H. Perlis
Roseann E. Peterson
Giorgio Pistis
Renato Polimanti
David J. Porteous
Danielle Posthuma
Jill A. Rabinowitz
Ted Reichborn-Kjennerud
Andreas Reif
Frances Rice
Roland Ricken
Marcella Rietschel
Margarita Rivera
Christian Rück
Giovanni A. Salum
Catherine Schaefer
Srijan Sen
Alessandro Serretti
Alkistis Skalkidou
Jordan W. Smoller
Dan J. Stein
Frederike Stein
Murray B. Stein
Patrick F. Sullivan
Martin Tesli
Thorgeir E. Thorgeirsson
Henning Tiemeier
Nicholas J. Timpson
Monica Uddin
Rudolf Uher
David A. van Heel
Karin J.H. Verweij
Robin G. Walters
Sylvia Wassertheil-Smoller
Jens R. Wendland
Thomas Werge
Aeilko H. Zwinderman
Karoline Kuchenbaecker
Naomi R. Wray
Stephan Ripke
Cathryn M. Lewis
Andrew M. McIntosh
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.
Subjects
GWAS
depression
drugs
enrichment
genetic
genome-wide association study
neurons
pharmacotherapies
targets
SDGs
Publisher
Elsevier BV
Type
journal article