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Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression. Am J Hum Genet 2021 Sep 02;108(9):1765-1779

Date

08/28/2021

Pubmed ID

34450030

Pubmed Central ID

PMC8456180

DOI

10.1016/j.ajhg.2021.07.013

Scopus ID

2-s2.0-85114108674 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

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.

Author List

Mo A, Nagpal S, Gettler K, Haritunians T, Giri M, Haberman Y, Karns R, Prince J, Arafat D, Hsu NY, Chuang LS, Argmann C, Kasarskis A, Suarez-Farinas M, Gotman N, Mengesha E, Venkateswaran S, Rufo PA, Baker SS, Sauer CG, Markowitz J, Pfefferkorn MD, Rosh JR, Boyle BM, Mack DR, Baldassano RN, Shah S, LeLeiko NS, Heyman MB, Griffiths AM, Patel AS, Noe JD, Davis Thomas S, Aronow BJ, Walters TD, McGovern DPB, Hyams JS, Kugathasan S, Cho JH, Denson LA, Gibson G

Author

Joshua D. Noe MD Associate Dean, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Biological Specimen Banks
Cohort Studies
Colectomy
Colitis, Ulcerative
Colon
Crohn Disease
Datasets as Topic
Disease Progression
Gene Expression Profiling
Genome-Wide Association Study
Humans
Multifactorial Inheritance
Prognosis
Quantitative Trait Loci
Risk Assessment
Transcriptome
United Kingdom