title: Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation.
abstract: 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 100 kb 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.
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Damien C
authors.initials: DC
authors.lastname: Croteau-Chonka
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Division of Pulmonary and Critical Care Medicine, School of Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Rogers
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGeachie
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Ziniti
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Stubbs
authors.affiliation: Departments of Biostatistics and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.affiliation: Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Strunk
authors.affiliation: University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Division of Allergy and Clinical Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Liu
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stranger
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Carey
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; BWH Pulmonary Genetics Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
mesh_terms: D000483:Alleles; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics*; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D040641:Quantitative Trait Loci