title: A Joint Location-Scale Test Improves Power to Detect Associated SNPs, Gene Sets, and Pathways.
abstract: Gene-based, pathway, and other multivariate association methods are motivated by the possibility of GxG and GxE interactions; however, accounting for such interactions is limited by the challenges associated with adequate modeling information. Here we propose an easy-to-implement joint location-scale (JLS) association testing framework for single-variant and multivariate analysis that accounts for interactions without explicitly modeling them. We apply the JLS method to a gene-set analysis of cystic fibrosis (CF) lung disease, which is influenced by multiple environmental and genetic factors. We identify and replicate an association between the constituents of the apical plasma membrane and CF lung disease (p = 0.0099 and p = 0.0180, respectively) and highlight a role for the SLC9A3-SLC9A3R1/2-EZR complex in contributing to CF lung disease. Many association studies could benefit from re-analysis with the JLS method that leverages complex genetic architecture for SNP, gene, and pathway identification. Analytical verification, simulation, and additional proof-of-principle applications support our approach.
authors.affiliation: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada; Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Soave
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Trousseau Hospital, Pediatric Pulmonology Department; Institut National de la Santé et la Recherche Médicale (INSERM), UMR_S 938, CDR Saint-Antoine, 75012 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, 75005 Paris, France.
authors.forename: Harriet
authors.initials: H
authors.lastname: Corvol
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Naim
authors.initials: N
authors.lastname: Panjwani
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Jiafen
authors.initials: J
authors.lastname: Gong
authors.affiliation: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada; Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Weili
authors.initials: W
authors.lastname: Li
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, 75005 Paris, France; AP-HP, Saint-Antoine Hospital, Biostatistics Department, INSERM, UMR_S 1136, 75012 Paris, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Boëlle
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.affiliation: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada; Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada. Electronic address: lisa.strug@utoronto.ca.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
authors.affiliation: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada; Department of Statistical Sciences, University of Toronto, Toronto, ON M5S 3G3, Canada. Electronic address: sun@utstat.toronto.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism; D048909:Diabetes Complications / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; D010750:Phosphoproteins; C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor
keywords: GxE interaction; GxG interaction; HbA1c level; complex traits; cystic fibrosis; multivariate model; pathway; type 1 diabetes; variance tests