title: Powerful Set-Based Gene-Environment Interaction Testing Framework for Complex Diseases.
abstract: Identification of gene-environment interaction (G × E) is important in understanding the etiology of complex diseases. Based on our previously developed Set Based gene EnviRonment InterAction test (SBERIA), in this paper we propose a powerful framework for enhanced set-based G × E testing (eSBERIA). The major challenge of signal aggregation within a set is how to tell signals from noise. eSBERIA tackles this challenge by adaptively aggregating the interaction signals within a set weighted by the strength of the marginal and correlation screening signals. eSBERIA then combines the screening-informed aggregate test with a variance component test to account for the residual signals. Additionally, we develop a case-only extension for eSBERIA (coSBERIA) and an existing set-based method, which boosts the power not only by exploiting the G-E independence assumption but also by avoiding the need to specify main effects for a large number of variants in the set. Through extensive simulation, we show that coSBERIA and eSBERIA are considerably more powerful than existing methods within the case-only and the case-control method categories across a wide range of scenarios. We conduct a genome-wide G × E search by applying our methods to Illumina HumanExome Beadchip data of 10,446 colorectal cancer cases and 10,191 controls and identify two novel interactions between nonsteroidal anti-inflammatory drugs (NSAIDs) and MINK1 and PTCHD3.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Shuo
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Sonja
authors.initials: S
authors.lastname: Berndt
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bézieau
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, United States of America.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Campbell
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|School of Public Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Ontario Institute for Cancer Research, Toronto, Canada.|Centre for Public Health Research, Massey University, Wellington, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, United States of America.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.affiliation: Discipline of Genetics, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Woods
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C558500:PTCHD3 protein, human; D011956:Receptors, Cell Surface; C497353:MINK1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: G × E screening statistics; GWAS; eSBERUA; rare variants