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Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat\u2013response 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 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 out of the 58 associations 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 implicated in ANX genetic risk. 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J.L.K. is a member of the Scientific Advisory Board for Myriad Neuroscience. I.B.H. was an inaugural commissioner on Australia\u2019s National Mental Health Commission (2012\u20132018). He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC), University of Sydney. The BMC operates early-intervention youth services at Camperdown under contract to Headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30M Australian Government-funded Project Synergy (2017\u20132020; a 3-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. A.M.M has received research support from Eli Lilly, Janssen and The Sackler Trust. A.M.M. has also received speaker fees from Illumina and Janssen. M.B.S. has, in the past 3\u2009years, received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals and Roche\/Genentech. M.B.S. has stock options in Oxeia Biopharmaceuticals and EpiVario. He is paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor) and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from the NIH, Department of Veterans Affairs and Department of Defense. He is on the scientific advisory board for the BBRF and the Anxiety and Depression Association of America. J. Gelernter is named as an inventor on PCT patent application no. 15\/878,640, entitled\u201c Genotype-guided dosing of opioid agonists\u201d, filed 24 January 2018 and issued 26 January 2021 as US Patent No. 10,900,082; he is also paid for editorial work for the journal \u201cComplex Psychiatry\u201d. I.H. received speaker\u2019s honoraria from Lundbeck. O.A.A. received speaker\u2019s honorarium from Lundbeck and Sunovion and served as a consultant for Cortechs.ai and Precision Health. K.D. has been a member of the Steering Committee of Neurosciences, Janssen, until 2022 and is currently a member of the Board of the German National Society of Psychiatry (DGPPN) and the Neurotorium Editorial Board of the Lundbeck Foundation. J.W.S. is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received an honorarium for an internal seminar at Tempus Labs. He is the principal investigator of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe, for which 23andMe provides analysis time as in-kind support but no payments. E.M. has received research support and has also received speaker fees from Lundbeck. H.J.G. has received travel grants and speaker\u2019s honoraria from Indorsia, Neuraxpharm, Servier and Janssen Cilag. H.L. has served as a speaker for Evolan Pharma, Medici and Shire\/Takeda and has received research grants from Shire\/Takeda; all outside of the submitted work. G.B. is an advisory board member for Compass Pathways. J.D. is a member of the board of the German Society of Biological Psychiatry and is on the scientific advisory boards of non-profit organizations and foundations. V.A. worked as an advisor for Sanofi-Adventis Germany. Z.F. and X. Wang are employees of 23andMe and hold stock or stock options in 23andMe. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}