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Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation
Disease-associated loci identified through genome-wide association studies (GWAS) frequently localize to non-coding sequence. We and others have demonstrated strong enrichment of such single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTLs), supporting an important role...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608673/ https://www.ncbi.nlm.nih.gov/pubmed/26474488 http://dx.doi.org/10.1371/journal.pone.0140758 |
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author | Croteau-Chonka, Damien C. Rogers, Angela J. Raj, Towfique McGeachie, Michael J. Qiu, Weiliang Ziniti, John P. Stubbs, Benjamin J. Liang, Liming Martinez, Fernando D. Strunk, Robert C. Lemanske, Robert F. Liu, Andrew H. Stranger, Barbara E. Carey, Vincent J. Raby, Benjamin A. |
author_facet | Croteau-Chonka, Damien C. Rogers, Angela J. Raj, Towfique McGeachie, Michael J. Qiu, Weiliang Ziniti, John P. Stubbs, Benjamin J. Liang, Liming Martinez, Fernando D. Strunk, Robert C. Lemanske, Robert F. Liu, Andrew H. Stranger, Barbara E. Carey, Vincent J. Raby, Benjamin A. |
author_sort | Croteau-Chonka, Damien C. |
collection | PubMed |
description | Disease-associated loci identified through genome-wide association studies (GWAS) frequently localize to non-coding sequence. We and others have demonstrated strong enrichment of such single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTLs), supporting an important role for regulatory genetic variation in complex disease pathogenesis. Herein we describe our initial efforts to develop a predictive model of disease-associated variants leveraging eQTL information. We first catalogued cis-acting eQTLs (SNPs within 100kb of target gene transcripts) by meta-analyzing four studies of three blood-derived tissues (n = 586). At a false discovery rate < 5%, we mapped eQTLs for 6,535 genes; these were enriched for disease-associated genes (P < 10(−04)), particularly those related to immune diseases and metabolic traits. Based on eQTL information and other variant annotations (distance from target gene transcript, minor allele frequency, and chromatin state), we created multivariate logistic regression models to predict SNP membership in reported GWAS. The complete model revealed independent contributions of specific annotations as strong predictors, including evidence for an eQTL (odds ratio (OR) = 1.2–2.0, P < 10(−11)) and the chromatin states of active promoters, different classes of strong or weak enhancers, or transcriptionally active regions (OR = 1.5–2.3, P < 10(−11)). This complete prediction model including eQTL association information ultimately allowed for better discrimination of SNPs with higher probabilities of GWAS membership (6.3–10.0%, compared to 3.5% for a random SNP) than the other two models excluding eQTL information. This eQTL-based prediction model of disease relevance can help systematically prioritize non-coding GWAS SNPs for further functional characterization. |
format | Online Article Text |
id | pubmed-4608673 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46086732015-10-29 Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation Croteau-Chonka, Damien C. Rogers, Angela J. Raj, Towfique McGeachie, Michael J. Qiu, Weiliang Ziniti, John P. Stubbs, Benjamin J. Liang, Liming Martinez, Fernando D. Strunk, Robert C. Lemanske, Robert F. Liu, Andrew H. Stranger, Barbara E. Carey, Vincent J. Raby, Benjamin A. PLoS One Research Article Disease-associated loci identified through genome-wide association studies (GWAS) frequently localize to non-coding sequence. We and others have demonstrated strong enrichment of such single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTLs), supporting an important role for regulatory genetic variation in complex disease pathogenesis. Herein we describe our initial efforts to develop a predictive model of disease-associated variants leveraging eQTL information. We first catalogued cis-acting eQTLs (SNPs within 100kb of target gene transcripts) by meta-analyzing four studies of three blood-derived tissues (n = 586). At a false discovery rate < 5%, we mapped eQTLs for 6,535 genes; these were enriched for disease-associated genes (P < 10(−04)), particularly those related to immune diseases and metabolic traits. Based on eQTL information and other variant annotations (distance from target gene transcript, minor allele frequency, and chromatin state), we created multivariate logistic regression models to predict SNP membership in reported GWAS. The complete model revealed independent contributions of specific annotations as strong predictors, including evidence for an eQTL (odds ratio (OR) = 1.2–2.0, P < 10(−11)) and the chromatin states of active promoters, different classes of strong or weak enhancers, or transcriptionally active regions (OR = 1.5–2.3, P < 10(−11)). This complete prediction model including eQTL association information ultimately allowed for better discrimination of SNPs with higher probabilities of GWAS membership (6.3–10.0%, compared to 3.5% for a random SNP) than the other two models excluding eQTL information. This eQTL-based prediction model of disease relevance can help systematically prioritize non-coding GWAS SNPs for further functional characterization. Public Library of Science 2015-10-16 /pmc/articles/PMC4608673/ /pubmed/26474488 http://dx.doi.org/10.1371/journal.pone.0140758 Text en © 2015 Croteau-Chonka et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Croteau-Chonka, Damien C. Rogers, Angela J. Raj, Towfique McGeachie, Michael J. Qiu, Weiliang Ziniti, John P. Stubbs, Benjamin J. Liang, Liming Martinez, Fernando D. Strunk, Robert C. Lemanske, Robert F. Liu, Andrew H. Stranger, Barbara E. Carey, Vincent J. Raby, Benjamin A. Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation |
title | Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation |
title_full | Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation |
title_fullStr | Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation |
title_full_unstemmed | Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation |
title_short | Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation |
title_sort | expression quantitative trait loci information improves predictive modeling of disease relevance of non-coding genetic variation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608673/ https://www.ncbi.nlm.nih.gov/pubmed/26474488 http://dx.doi.org/10.1371/journal.pone.0140758 |
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