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