@article{4d980f7f7c5b41029e267514bf2ac7a3,
title = "Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression",
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.",
keywords = "cell-type-specific gene expression, eQTLs, predicted polygenic transcriptional risk scores, prediction of disease progression, transcriptional risk scores, transcriptome-wide association studies",
author = "Angela Mo and Sini Nagpal and Kyle Gettler and Talin Haritunians and Mamta Giri and Yael Haberman and Rebekah Karns and Jarod Prince and Dalia Arafat and Hsu, {Nai Yun} and Chuang, {Ling Shiang} and Carmen Argmann and Andrew Kasarskis and Mayte Suarez-Farinas and Nathan Gotman and Emebet Mengesha and Suresh Venkateswaran and Rufo, {Paul A.} and Baker, {Susan S.} and Sauer, {Cary G.} and James Markowitz and Pfefferkorn, {Marian D.} and Rosh, {Joel R.} and Boyle, {Brendan M.} and Mack, {David R.} and Baldassano, {Robert N.} and Sapana Shah and LeLeiko, {Neal S.} and Heyman, {Melvin B.} and Griffiths, {Anne M.} and Patel, {Ashish S.} and Noe, {Joshua D.} and {Davis Thomas}, Sonia and Aronow, {Bruce J.} and Walters, {Thomas D.} and McGovern, {Dermot P.B.} and Hyams, {Jeffrey S.} and Subra Kugathasan and Cho, {Judy H.} and Denson, {Lee A.} and Greg Gibson",
note = "Funding Information: Support for this study was provided by NIDDK through grants U01DK095745, R01DK119991, P01DK046763, U01DK062413, U24DK062429, and U01DK062422 as well as the Leona M. and Harry B. Helmsley Charitable Trust. The authors thank Urko Marigorta for his counsel in development of TRS and Frank Hamilton, Dana Anderson, James Everhart, Jose Serrano, and Stephen James from NIDDK for their guidance. This research has been conducted with the UK Biobank resource under application number 17984 to G.G. The authors thank PROTECT site investigators for patient recruitment and data gathering, the research coordinators at the investigative sites for their tireless attention, and the affected individuals and families who graciously agreed to participate. 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. Funding Information: Support for this study was provided by NIDDK through grants U01DK095745 , R01DK119991 , P01DK046763 , U01DK062413 , U24DK062429 , and U01DK062422 as well as the Leona M. and Harry B. Helmsley Charitable Trust . The authors thank Urko Marigorta for his counsel in development of TRS and Frank Hamilton, Dana Anderson, James Everhart, Jose Serrano, and Stephen James from NIDDK for their guidance. This research has been conducted with the UK Biobank resource under application number 17984 to G.G. The authors thank PROTECT site investigators for patient recruitment and data gathering, the research coordinators at the investigative sites for their tireless attention, and the affected individuals and families who graciously agreed to participate. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = sep,
day = "2",
doi = "10.1016/j.ajhg.2021.07.013",
language = "English",
volume = "108",
pages = "1765--1779",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "9",
}