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

Urko M. Marigorta, Lee A. Denson, Jeffrey S. Hyams, Kajari Mondal, Jarod Prince, Thomas D. Walters, Anne Griffiths, Joshua D. Noe, Wallace V. Crandall, Joel Rosh, David R. Mack, Richard Kellermayer, Melvin B. Heyman, Susan S. Baker, Michael C. Stephens, Robert N. Baldassano, James F. Markowitz, Mi Ok Kim, Marla C. Dubinsky, Judy Cho & 3 others Bruce J. Aronow, Subra Kugathasan, Greg Gibson

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology1,2. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest2, we hypothesized that summation of risk-alleleassociated 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 disease3,4. 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.

Original languageEnglish (US)
Pages (from-to)1517-1521
Number of pages5
JournalNature Genetics
Volume49
Issue number10
DOIs
StatePublished - Oct 1 2017
Externally publishedYes

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Genome-Wide Association Study
Crohn Disease
Quantitative Trait Loci
Precision Medicine
Nucleic Acid Regulatory Sequences
Gene Expression Profiling
Inflammatory Bowel Diseases
Genes
Dissection
Cohort Studies
RNA
Pediatrics
Phenotype
Gene Expression

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Marigorta, U. M., Denson, L. A., Hyams, J. S., Mondal, K., Prince, J., Walters, T. D., ... Gibson, G. (2017). Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease. Nature Genetics, 49(10), 1517-1521. https://doi.org/10.1038/ng.3936
Marigorta, Urko M. ; Denson, Lee A. ; Hyams, Jeffrey S. ; Mondal, Kajari ; Prince, Jarod ; Walters, Thomas D. ; Griffiths, Anne ; Noe, Joshua D. ; Crandall, Wallace V. ; Rosh, Joel ; Mack, David R. ; Kellermayer, Richard ; Heyman, Melvin B. ; Baker, Susan S. ; Stephens, Michael C. ; Baldassano, Robert N. ; Markowitz, James F. ; Kim, Mi Ok ; Dubinsky, Marla C. ; Cho, Judy ; Aronow, Bruce J. ; Kugathasan, Subra ; Gibson, Greg. / Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease. In: Nature Genetics. 2017 ; Vol. 49, No. 10. pp. 1517-1521.
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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 pathology1,2. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest2, we hypothesized that summation of risk-alleleassociated 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 disease3,4. 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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Marigorta, UM, Denson, LA, Hyams, JS, Mondal, K, Prince, J, Walters, TD, Griffiths, A, Noe, JD, Crandall, WV, Rosh, J, Mack, DR, Kellermayer, R, Heyman, MB, Baker, SS, Stephens, MC, Baldassano, RN, Markowitz, JF, Kim, MO, Dubinsky, MC, Cho, J, Aronow, BJ, Kugathasan, S & Gibson, G 2017, 'Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease', Nature Genetics, vol. 49, no. 10, pp. 1517-1521. https://doi.org/10.1038/ng.3936

Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease. / Marigorta, Urko M.; Denson, Lee A.; Hyams, Jeffrey S.; Mondal, Kajari; Prince, Jarod; Walters, Thomas D.; Griffiths, Anne; Noe, Joshua D.; Crandall, Wallace V.; Rosh, Joel; Mack, David R.; Kellermayer, Richard; Heyman, Melvin B.; Baker, Susan S.; Stephens, Michael C.; Baldassano, Robert N.; Markowitz, James F.; Kim, Mi Ok; Dubinsky, Marla C.; Cho, Judy; Aronow, Bruce J.; Kugathasan, Subra; Gibson, Greg.

In: Nature Genetics, Vol. 49, No. 10, 01.10.2017, p. 1517-1521.

Research output: Contribution to journalArticle

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AU - Denson, Lee A.

AU - Hyams, Jeffrey S.

AU - Mondal, Kajari

AU - Prince, Jarod

AU - Walters, Thomas D.

AU - Griffiths, Anne

AU - Noe, Joshua D.

AU - Crandall, Wallace V.

AU - Rosh, Joel

AU - Mack, David R.

AU - Kellermayer, Richard

AU - Heyman, Melvin B.

AU - Baker, Susan S.

AU - Stephens, Michael C.

AU - Baldassano, Robert N.

AU - Markowitz, James F.

AU - Kim, Mi Ok

AU - Dubinsky, Marla C.

AU - Cho, Judy

AU - Aronow, Bruce J.

AU - Kugathasan, Subra

AU - Gibson, Greg

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N2 - Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology1,2. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest2, we hypothesized that summation of risk-alleleassociated 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 disease3,4. 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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Marigorta UM, Denson LA, Hyams JS, Mondal K, Prince J, Walters TD et al. Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease. Nature Genetics. 2017 Oct 1;49(10):1517-1521. https://doi.org/10.1038/ng.3936