Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling
Authors: Strom Nora I. , Verhulst Brad , Bacanu Silviu-Alin , Cheesman Rosa , Purves Kirstin L. , Gedik Hüseyin , Mitchell Brittany L. , Kwong Alex S. , Faucon Annika B. , Singh Kritika , Medland Sarah , Colodro-Conde Lucia , Krebs Kristi , Hoffmann Per , Herms Stefan , Gehlen Jan , Ripke Stephan , Awasthi Swapnil , Palviainen Teemu , Tasanko Elisa M. , Peterson Roseann E. , Adkins Daniel E. , Shabalin Andrey A. , Adams Mark J. , Iveson Matthew H. , Campbell Archie , Thomas Laurent F. , Winsvold Bendik S. , Drange Ole Kristian , Børte Sigrid , ter Kuile Abigail R. , Nguyen Tan-Hoang , Meier Sandra M. , Corfield Elizabeth C. , Hannigan Laurie , Levey Daniel F. , Czamara Darina , Weber Heike , Choi Karmel W. , Pistis Giorgio , Couvy-Duchesne Baptiste , Van der Auwera Sandra , Teumer Alexander , Karlsson Robert , Garcia-Argibay Miguel , Lee Donghyung , Wang Rujia , Bjerkeset Ottar , Stordal Eystein , Bäckmann Julia , Salum Giovanni A. , Zai Clement C. , Kennedy James L. , Zai Gwyneth , Tiwari Arun K. , Heilmann-Heimbach Stefanie , Schmidt Börge , Kaprio Jaakko , Kennedy Martin M. , Boden Joseph , Havdahl Alexandra , Middeldorp Christel M. , Lopes Fabiana L. , Akula Nirmala , McMahon Francis J. , Binder Elisabeth B. , Fehm Lydia , Ströhle Andreas , Castelao Enrique , Tiemeier Henning , Stein Dan J. , Whiteman David , Olsen Catherine , Fuller Zachary , Wang Xin , Wray Naomi R. , Byrne Enda M. , Lewis Glyn , Timpson Nicholas J. , Davis Lea K. , Hickie Ian B. , Gillespie Nathan A. , Milani Lili , Schumacher Johannes , Woldbye David P. , Forstner Andreas J. , Nöthen Markus M. , Hovatta Iiris , Horwood John , Copeland William E. , Maes Hermine H. , McIntosh Andrew M. , Andreassen Ole A. , Zwart John-Anker , Mors Ole , Børglum Anders D. , Mortensen Preben B. , Ask Helga , Reichborn-Kjennerud Ted , Najman Jackob M. , Stein Murray B. , Gelernter Joel , Milaneschi Yuri , Penninx Brenda W. , Boomsma Dorret I. , Maron Eduard , Erhardt-Lehmann Angelika , Rück Christian , Kircher Tilo T. , Melzig Christiane A. , Alpers Georg W. , Arolt Volker , Domschke Katharina , Smoller Jordan W. , Preisig Martin , Martin Nicholas G. , Lupton Michelle K. , Luik Annemarie I. , Reif Andreas , Grabe Hans J. , Larsson Henrik , Magnusson Patrik K. , Oldehinkel Albertine J. , Hartman Catharina A. , Breen Gerome , Docherty Anna R. , Coon Hilary , Conrad Rupert , Lehto Kelli ,   the Million Veteran Program; FinnGen; 23andMe, Deckert Jürgen , Eley Thalia C. , Mattheisen Manuel , Hettema John M. 
Published: July 2024

AbstractThe 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.