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Background: The longitudinal relation between coronary artery disease (CAD) polygenic risk score (PRS) and long-term plaque progression and high-risk plaque (HRP) features is unknown., Objectives: The goal of this study was to investigate the impact of CAD PRS on long-term coronary plaque progression and HRP., Methods: Patients underwent CAD PRS measurement and prospective serial coronary computed tomography angiography (CTA) imaging. Coronary CTA scans were analyzed with a previously validated artificial intelligence-based algorithm (atherosclerosis imaging-quantitative computed tomography imaging). The relationship between CAD PRS and change in percent atheroma volume (PAV), percent noncalcified plaque progression, and HRP prevalence was investigated in linear mixed-effect models adjusted for baseline plaque volume and conventional risk factors., Results: A total of 288 subjects (mean age 58 ± 7 years; 60% male) were included in this study with a median scan interval of 10.2 years. At baseline, patients with a high CAD PRS had a more than 5-fold higher PAV than those with a low CAD PRS (10.4% vs 1.9%; P < 0.001). Per 10 years of follow-up, a 1 SD increase in CAD PRS was associated with a 0.69% increase in PAV progression in the multivariable adjusted model. CAD PRS provided additional discriminatory benefit for above-median noncalcified plaque progression during follow-up when added to a model with conventional risk factors (AUC: 0.73 vs 0.69; P = 0.039). Patients with high CAD PRS had an OR of 2.85 (95% CI: 1.14-7.14; P = 0.026) and 6.16 (95% CI: 2.55-14.91; P < 0.001) for having HRP at baseline and follow-up compared with those with low CAD PRS., Conclusions: Polygenic risk is strongly associated with future long-term plaque progression and HRP in patients suspected of having CAD., Competing Interests: Funding Support and Author Disclosures Dr Nurmohamed is supported by grants from the Dutch Heart Foundation (Dekker grant number 03-007-2023-0068) and European Atherosclerosis Society (2023). Dr Fahed is supported by grants K08HL161448 and R01HL164629 from the National Heart, Lung, and Blood Institute. Dr Nurmohamed has received research funding/speaker fees from Cleerly, Daiichi Sankyo, and Novartis; and is co-founder of Lipid Tools. Dr Choi has received grant support from Cleerly Inc and GW Heart and Vascular Institute; has equity in Cleerly, Inc; and reports consulting with Siemens Healthineers. Dr Natarajan has received investigator-initiated grants from Allelica, Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; has received personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, GV, HeartFlow, Novartis, and Roche/Genentech; is a co-founder of TenSixteen Bio; is a scientific advisory board member of Esperion Therapeutics, Preciseli, and TenSixteen Bio; and reports spousal employment at Vertex Pharmaceuticals. Drs Earls and Min are employees of and hold equity in Cleerly Inc. Dr Stroes has received lecturing/advisory board fees from Amgen, Novartis, Esperion, Sanofi-Regeneron, and Akcea. Dr Knaapen has received research grants from HeartFlow, Inc and Cleerly Inc. Dr Reeskamp is cofounder of Lipid Tools; and has received speaker fees from Novartis, Daiichi Sankyo, and Ultragenyx. Dr Fahed is co-founder of Goodpath. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)