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An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications., Competing Interests: Declaration of interests J.S.H. has served on an advisory board for Janssen and is acting as a consultant for AbbVie, Takeda, Lilly, Boehringer-Ingelheim, Allergan, Pfizer, Receptos, and AstraZeneca. S.D.T. has been a member of an independent data monitoring committee for Lycera Corporation. A.M.G. has received research support from AbbVie; been a consultant for AbbVie, Celgene, Janssen, Lilly, Pfizer, and Takeda; and been a speaker for AbbVie, Janssen, and Shire. N.S.L. has been a consultant for AbbVie. C.G.S. has been a consultant for AbbVie. J.M. has been a consultant for Janssen, Celgene, and Lilly. J.R.R. has been a consultant for AbbVie, Celgene, Janssen, Luitpold, and Pfizer and received grant funding from Janssen and AbbVie. A.S.P. has participated in speakers bureaus for AbbVie and Janssen. M.B.H. has received research grants from Genentech, AbbVie, Shire, Takeda, Mallinkrodt, Janssen, and Gilead. P.A.R. has been a consultant for Shire and Leutpold; been a speaker for AbbVie; and received research support from TechLab. S.K. has been a consultant for Janssen and UCB. L.A.D. has received grant support from AbbVie and Janssen. D.P.B.M. and T.H. are faculty members at Cedars-Sinai Medical Center. E.M. is an employee at Cedars-Sinai. Cedars-Sinai has financial interests in Prometheus Biosciences, a company that has access to the data and specimens in Cedars-Sinai’s MIRIAD Biobank. Prometheus Biosciences seeks to develop commercial products. D.M. is a paid consultant and shareholder of Prometheus Biosciences. D.M. has consulted for Pfizer, Gilead, Palatin Technologies, Bridge Biotherapeutics, and Takeda. All other authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)