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Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling.

medRxiv : the preprint server for health sciences

Authors: Nora I Strom, Brad Verhulst, Silviu-Alin Bacanu, Rosa Cheesman, Kirstin L Purves, Hüseyin Gedik, Brittany L Mitchell, Alex S Kwong, Annika B Faucon, Kritika Singh, Sarah Medland, Lucia Colodro-Conde, Kristi Krebs, Per Hoffmann, Stefan Herms, Jan Gehlen, Stephan Ripke, Swapnil Awasthi, Teemu Palviainen, Elisa M Tasanko, Roseann E Peterson, Daniel E Adkins, Andrey A Shabalin, Mark J Adams, Matthew H Iveson, Archie Campbell, Laurent F Thomas, Bendik S Winsvold, Ole Kristian Drange, Sigrid Børte, Abigail R Ter Kuile, Tan-Hoang Nguyen, Sandra M Meier, Elizabeth C Corfield, Laurie Hannigan, Daniel F Levey, Darina Czamara, Heike Weber, Karmel W Choi, Giorgio Pistis, Baptiste Couvy-Duchesne, Sandra Van der Auwera, Alexander Teumer, Robert Karlsson, Miguel Garcia-Argibay, Donghyung Lee, Rujia Wang, Ottar Bjerkeset, Eystein Stordal, Julia Bäckmann, Giovanni A Salum, Clement C Zai, James L Kennedy, Gwyneth Zai, Arun K Tiwari, Stefanie Heilmann-Heimbach, Börge Schmidt, Jaakko Kaprio, Martin M Kennedy, Joseph Boden, Alexandra Havdahl, Christel M Middeldorp, Fabiana L Lopes, Nirmala Akula, Francis J McMahon, Elisabeth B Binder, Lydia Fehm, Andreas Ströhle, Enrique Castelao, Henning Tiemeier, Dan J Stein, David Whiteman, Catherine Olsen, Zachary Fuller, Xin Wang, Naomi R Wray, Enda M Byrne, Glyn Lewis, Nicholas J Timpson, Lea K Davis, Ian B Hickie, Nathan A Gillespie, Lili Milani, Johannes Schumacher, David P Woldbye, Andreas J Forstner, Markus M Nöthen, Iiris Hovatta, John Horwood, William E Copeland, Hermine H Maes, Andrew M McIntosh, Ole A Andreassen, John-Anker Zwart, Ole Mors, Anders D Børglum, Preben B Mortensen, Helga Ask, Ted Reichborn-Kjennerud, Jackob M Najman, Murray B Stein, Joel Gelernter, Yuri Milaneschi, Brenda W Penninx, Dorret I Boomsma, Eduard Maron, Angelika Erhardt-Lehmann, Christian Rück, Tilo T Kircher, Christiane A Melzig, Georg W Alpers, Volker Arolt, Katharina Domschke, Jordan W Smoller, Martin Preisig, Nicholas G Martin, Michelle K Lupton, Annemarie I Luik, Andreas Reif, Hans J Grabe, Henrik Larsson, Patrik K Magnusson, Albertine J Oldehinkel, Catharina A Hartman, Gerome Breen, Anna R Docherty, Hilary Coon, Rupert Conrad, Kelli Lehto, Jürgen Deckert, Thalia C Eley, Manuel Mattheisen, John M Hettema

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

PMID: 39006447

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