title: An interaction quantitative trait loci tool implicates epistatic functional variants in an apoptosis pathway in smallpox vaccine eQTL data.
abstract: Expression quantitative trait loci (eQTL) studies have functionalized nucleic acid variants through the regulation of gene expression. Although most eQTL studies only examine the effects of single variants on transcription, a more complex process of variant-variant interaction (epistasis) may regulate transcription. Herein, we describe a tool called interaction QTL (iQTL) designed to efficiently detect epistatic interactions that regulate gene expression. To maximize biological relevance and minimize the computational and hypothesis testing burden, iQTL restricts interactions such that one variant is within a user-defined proximity of the transcript (cis-regulatory). We apply iQTL to a data set of 183 smallpox vaccine study participants with genome-wide association study and gene expression data from unstimulated samples and samples stimulated by inactivated vaccinia virus. While computing only 0.15% of possible interactions, we identify 11 probe sets whose expression is regulated through a variant-variant interaction. We highlight the functional epistatic interactions among apoptosis-related genes, DIABLO, TRAPPC4 and FADD, in the context of smallpox vaccination. We also use an integrative network approach to characterize these iQTL interactions in a posterior network of known prior functional interactions. iQTL is an efficient, open-source tool to analyze variant interactions in eQTL studies, providing better understanding of the function of epistasis in immune response and other complex phenotypes.
authors.affiliation: Department of Biostatistics, Harvard University, Cambridge, MA, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Lareau
authors.affiliation: Department of Mathematics, Tandy School of Computer Science, University of Tulsa, Tulsa, OK, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: White
authors.affiliation: Department of Health Services Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Clinical Vaccine Research Group, Mayo Clinic, Rochester, MN, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Kennedy
authors.affiliation: Clinical Vaccine Research Group, Mayo Clinic, Rochester, MN, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Poland
authors.affiliation: Department of Mathematics, Tandy School of Computer Science, University of Tulsa, Tulsa, OK, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: McKinney
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D004843:Epistasis, Genetic; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D012899:Smallpox / Q000235:genetics* / Q000276:immunology; D012900:Smallpox Vaccine / Q000276:immunology; D012984:Software; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D012900:Smallpox Vaccine; D033921:Vesicular Transport Proteins