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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.
41 Authors
Angela Mo
Sini Nagpal
Kyle Gettler
Talin Haritunians
Mamta Giri
Yael Haberman
Rebekah Karns
Jarod Prince
Dalia Arafat
Nai-Yun Hsu
Ling-Shiang Chuang
Carmen Argmann
Andrew Kasarskis
Mayte Suarez-Farinas
Nathan Gotman
Emebet Mengesha
Suresh Venkateswaran
Paul A Rufo
Susan S Baker
Cary G Sauer
James Markowitz
Marian D Pfefferkorn
Joel R Rosh
Brendan M Boyle
David R Mack
Robert N Baldassano
Sapana Shah
Neal S LeLeiko
Melvin B Heyman
Anne M Griffiths
Ashish S Patel
Joshua D Noe
Sonia Davis Thomas
Bruce J Aronow
Thomas D Walters
Dermot P B McGovern
Jeffrey S Hyams
Subra Kugathasan
Judy H Cho
Lee A Denson
Greg Gibson
Enabling scientific discoveries that improve human health