title: Screening for interaction effects in gene expression data.
abstract: Expression quantitative trait (eQTL) studies are a powerful tool for identifying genetic variants that affect levels of messenger RNA. Since gene expression is controlled by a complex network of gene-regulating factors, one way to identify these factors is to search for interaction effects between genetic variants and mRNA levels of transcription factors (TFs) and their respective target genes. However, identification of interaction effects in gene expression data pose a variety of methodological challenges, and it has become clear that such analyses should be conducted and interpreted with caution. Investigating the validity and interpretability of several interaction tests when screening for eQTL SNPs whose effect on the target gene expression is modified by the expression level of a transcription factor, we characterized two important methodological issues. First, we stress the scale-dependency of interaction effects and highlight that commonly applied transformation of gene expression data can induce or remove interactions, making interpretation of results more challenging. We then demonstrate that, in the setting of moderate to strong interaction effects on the order of what may be reasonably expected for eQTL studies, standard interaction screening can be biased due to heteroscedasticity induced by true interactions. Using simulation and real data analysis, we outline a set of reasonable minimum conditions and sample size requirements for reliable detection of variant-by-environment and variant-by-TF interactions using the heteroscedasticity consistent covariance-based approach.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rice
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.|Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France.
authors.forename: Hugues
authors.identifier: http://orcid.org/0000-0002-7554-6783
authors.initials: H
authors.lastname: Aschard
mesh_terms: D015870:Gene Expression; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger