Aims: Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear., Methods and Results: A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan-Meier event rates, adjusted hazard ratios (HRs), C-indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32-1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99-3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C-index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS., Conclusion: In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP., Competing Interests: Conflict of interest: N.A.M. reports grant support from the National Institutes of Health and involvement in clinical trials with Amgen, Pfizer, Novartis, AstraZeneca, and Ionis without personal fees, payments, or increase in salary. A.C.G., F.K.K., and G.M.M. report no disclosures. C.R. is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. P.J. reports research support from Abbott Laboratories, Amgen, Inc., AstraZeneca, LP, Daiichi-Sankyo, Inc., Eisai, Inc., GlaxoSmithKline, Merck & Co., Inc., Regeneron Pharmaceuticals, Inc., Roche Diagnostics Corporation, Siemens Healthineers, Takeda Global Research and Development Center, and Waters Technologies Corporation, and consulting fees from Roche Diagnostics Corporation. D.D.B. is supported by Harvard Catalyst KL2/CMeRIT (NIH/NCATS UL 1TR002541) and has received research grant support to his institution from AstraZeneca and Pfizer and consulting fees from AstraZeneca. D.L.B. reports grants from AstraZeneca, during the conduct of the study; grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Garmin, Owkin, HLS Therapeutics, Eisai, Ethicon, Medtronic, 89Bio, sanofi aventis, Contego Medical, The Medicines Company, Roche, Pfizer, Forest Laboratories/AstraZeneca, Stasys, Ischemix, Amgen, Lilly, Chiesi, Ironwood, Merck, Abbott, Regeneron, Idorsia, Faraday Pharmaceuticals, Javelin, Reid Hoffman Foundation, Moderna, Beren, Aker Biomarine, Recardio, Acesion Pharma, Synaptic, Fractyl, Afimmune, Ferring Pharmaceuticals, Lexicon; other from FlowCo, Clinical Cardiology, VA, Takeda, Endotronix, Vascular Solutions, and Svelte, grants and other from PLx Pharma, Novartis, NirvaMed, MyoKardia/BMS, Janssen, Novo Nordisk, Cardax, and Boston Scientific, PhaseBio, Novo Nordisk, Cereno Scientific, CellProthera; personal fees from Duke Clinical Research Institute, Oakstone CME, High Enroll, Bristol-Myers Squibb, Mayo Clinic, Arnold and Porter law firm, Piper Sandler, Cowen and Company, Assistance Publique-Hôpitaux de Paris, Rutgers University, Wiley, AngioWave, K2P, Canadian Medical and Surgical Knowledge Translation Research Group, Journal of the American College of Cardiology, TobeSoft, Bayer, MJH Life Sciences, Level Ex, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), HMP Global, Cleveland Clinic, Mount Sinai School of Medicine, Medtelligence/ReachMD, CSL Behring; personal fees from from DRS. LINQ, non-financial support, and other from American College of Cardiology; other from Medscape Cardiology, Philips, Regado Biosciences, Boston VA Research Institute, St. Jude Medical (now Abbott), Biotronik, CSI; personal fees and non-financial support from Society of Cardiovascular Patient Care; non-financial support from American Heart Association; grants, personal fees, and other from Boehringer Ingelheim, outside the submitted work. M.P.B. discloses grant support from Amgen, AstraZeneca, Bayer, and Sanofi and consulting fees from Amgen, AstraZeneca, Bayer, and Sanofi. C.P.C. reports research grants from Amgen, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi-Sankyo, Janssen, Merck, Novo Nordisk, and Pfizer. Consulting fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, Rhoshan, and Sanofi. R.P.G. reports grants from Amgen and Daiichi-Sankyo, during the conduct of the study; personal fees from Akcea, GlaxoSmithKline, Janssen, Lexicon, American College of Cardiology, Bristol-Myers Squibb, CVS Caremark, Pfizer, Servier, outside the submitted work; grants and personal fees from Amarin, Daiichi-Sankyo, Merck, Amgen; and Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital for research he is not directly involved in from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. M.L.O. reports institutional research grants from Amgen, Janssen, The Medicines Company, Eisai, GlaxoSmithKline, and Astra Zeneca. I.R. received personal fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Concenter BioPharma, and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FutuRx, Insuline Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novartis, Teva, GlucoMe, and DarioHealth. B.M.S. reports research grants from AstraZeneca, Eisai, Novartis, and Merck and consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr Reddy’s Laboratories, Eisai, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, Novo Nordisk, Sanofi, and St Jude’s Medical; and has equity in Health [at] Scale. E.B. reports research grants through the Brigham and Women’s Hospital from Astra Zeneca, Daiichi-Sankyo, Merck, and Novartis. Consultancies with Amgen, Cardurion, MyoKardia, NovoNordisk, Boehringer Ingelheim/Lilly, IMMEDIATE, and Verve. Uncompensated consultancies and lectures with The Medicines Company. D.A.M. reports grants to Brigham and Women’s Hospital from Abbott Laboratories, AstraZeneca, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Medicines Company, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche Diagnostics, Takeda, and Zora Biosciences. He has received consulting fees from Aralez, AstraZeneca, Bayer Pharma, InCarda, Novartis, and Roche Diagnostics. P.T.E. receives sponsored research support from Bayer AG and IBM Health, and he has consulted for Bayer AG, Novartis, MyoKardia, and Quest Diagnostics. S.A.L. receives sponsored research support from Bristol-Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM and has consulted for Bristol-Myers Squibb/Pfizer, Bayer AG, and Blackstone Life Sciences. Dr. Lubitz is supported by NIH grants R01HL139731, R01HL157635 and American Heart Association 18SFRN34250007. C.T.R. Honoraria; Modest; Bristol-Myers Squib, Pfizer, Portola, Honoraria; Significant; Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Janssen, Research Grant; Modest; Daiichi-Sankyo, MedImmune, National Institute of Health, Research Grant; Significant; Boehringer Ingelheim. M.S.S.: Other; Modest; Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, IFM Therapeutics, Intarcia, Medicines Company, MedImmune, Merck, Other; Significant; Amgen, Research Grant; Significant; Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai; Intarcia, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)