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Cited by 166Inflammatory Bowel DiseaseGenetic Associations and EpidemiologyMultiple Sclerosis Research Studies

Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease

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Marigorta, Urko M, Denson, Lee A, Hyams, Jeffrey S, Mondal, Kajari, Prince, Jarod, Walters, Thomas D, Griffiths, Anne, Noe, Joshua D +15 more·2017·Nature Genetics
DOI 10.1038/ng.3936PMC PMC5745037
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Abstract

Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest, we hypothesized that summation of risk-allele-associated gene expression, namely a transcriptional risk score (TRS), should provide accurate estimates of disease risk. We integrate summary-level GWAS and expression quantitative trait locus (eQTL) data with RNA-seq data from the RISK study, an inception cohort of pediatric Crohn's disease. We show that TRSs based on genes regulated by variants linked to inflammatory bowel disease (IBD) not only outperform genetic risk scores (GRSs) in distinguishing Crohn's disease from healthy samples, but also serve to identify patients who in time will progress to complicated disease. Our dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion versus protection, thereby linking statistical association to biological mechanism. The TRS approach constitutes a potential strategy for personalized medicine that enhances inference from static genotypic risk assessment.

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  • The study developed a proteomic risk score by selecting PWAS-significant aptamers (n=456) and performing LASSO regression to select predictors of AD status (Npredictors=100) in a training dataset (n=1,325).

    “We developed a proteomic risk score91 by selecting PWAS-significant aptamers (n=456) and performing LASSO regression to select predictors of AD status (Npredictors=100) in a training dataset (n=1,325).”

    From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [91]

    The Introductory Paragraph describes a transcriptional risk score derived from gene expression for predicting Crohn’s disease outcomes, providing a precedent for a molecular risk score. It does not describe a proteomic score, PWAS-significant aptamers, LASSO selection, Alzheimer’s disease status, or the stated predictor and training-set counts; those details concern the citing authors’ study, not this source. (LLM, conf=0.86)

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Authors
Marigorta, U. M., Denson, L. A., Hyams, J. S., Mondal, K., Prince, J., Walters, T. D., Griffiths, A., Noe, J. D., Crandall, W. V., Rosh, J. R., Mack, D. R., Kellermayer, R., Heyman, M. B., Baker, S. S., Stephens, M. C., Baldassano, R. N., Markowitz, J. F., Kim, M.-O., Dubinsky, M. C., Cho, J., Aronow, B. J., Kugathasan, S., & Gibson, G.
Affiliations
  • Georgia Institute of Technology (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • Connecticut Children's Medical Center (US)
  • Emory University (US)
  • University of Toronto (CA)
  • Medical College of Wisconsin (US)
  • Nationwide Children's Hospital (US)
  • Goryeb Children's Hospital (US)
  • University of Ottawa (CA)
  • University of California, San Francisco (US)
  • University at Buffalo, State University of New York (US)
  • Mayo Clinic (US)
  • University of Pennsylvania (US)
  • Northwell Health (US)
  • Mount Sinai Hospital (US)
Corresponding author
Gibson, Greg
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2017-08-14
Volume
49
Issue
10
Pages
1517-1521
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3936
PMC
PMC5745037
OpenAlex
W2746163443
Cited by
166
References
6
Citations by year
2026: 10 · 2025: 14 · 2024: 18 · 2023: 20 · 2022: 11 · 2021: 27 · 2020: 12 · 2019: 31 · 2018: 20 · 2017: 3
FWCI
11.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Crohn's and Colitis Foundation (274356, 292052, 419130)
  • National Institute of General Medical Sciences (P01GM099568)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK078392)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
Crohn's disease, expression quantitative trait loci, polygenic risk score, pediatric inflammatory bowel disease, disease progression prediction, gene expression, regulatory variants, personalized medicine, risk research
MeSH terms
Alleles, Child, Crohn Disease, Gene Expression Regulation, Humans, Ileum, Models, Genetic, Prognosis, RNA, Messenger, Transcription, Genetic, Inflammatory Bowel Diseases, Age of Onset, Disease Progression, Risk Assessment, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression Profiling, Quantitative Trait Loci, Genome-Wide Association Study, Observational Studies as Topic, Datasets as Topic

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