title: Genome-wide association interaction analysis for Alzheimer's disease.
abstract: We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = -0.19, p = 0.0006) and cerebellum (β = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach.
authors: Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Belgium. Electronic address: egusareva@ulg.ac.be.
authors: Elena S
authors: ES
authors: Gusareva
authors: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors: Minerva M
authors: MM
authors: Carrasquillo
authors: INSERM U744, Lille, France; Department of Public Health and Molecular Epidemiology of Aging Related Diseases, Institut Pasteur de Lille, Lille, France; Universite de Lille Nord de France, Lille, France.
authors: Céline
authors: C
authors: Bellenguez
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Department of Neurology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Elise
authors: E
authors: Cuyvers
authors: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors: Samuel
authors: S
authors: Colon
authors: Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
authors: Neill R
authors: NR
authors: Graff-Radford
authors: Department of Neurology, Mayo Clinic Florida, Rochester, MN, USA.
authors: Ronald C
authors: RC
authors: Petersen
authors: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors: Dennis W
authors: DW
authors: Dickson
authors: Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Belgium.
authors: Jestinah M
authors: JM
authors: Mahachie John
authors: Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Belgium.
authors: Kyrylo
authors: K
authors: Bessonov
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Department of Neurology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
authors: Denise
authors: D
authors: Harold
authors: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
authors: Julie
authors: J
authors: Williams
authors: INSERM U744, Lille, France; Department of Public Health and Molecular Epidemiology of Aging Related Diseases, Institut Pasteur de Lille, Lille, France; Universite de Lille Nord de France, Lille, France.
authors: Philippe
authors: P
authors: Amouyel
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Department of Neurology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Kristel
authors: K
authors: Sleegers
authors: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
authors: Nilüfer
authors: N
authors: Ertekin-Taner
authors: INSERM U744, Lille, France; Department of Public Health and Molecular Epidemiology of Aging Related Diseases, Institut Pasteur de Lille, Lille, France; Universite de Lille Nord de France, Lille, France.
authors: Jean-Charles
authors: JC
authors: Lambert
authors: Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Belgium.
authors: Kristel
authors: K
authors: Van Steen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D002531:Cerebellum; D015331:Cohort Studies; D003459:Crystallins / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D016601:RNA-Binding Proteins / Q000235:genetics; D013702:Temporal Lobe
chemical_list: C472003:CRYL1 protein, human; D003459:Crystallins; C485572:KHDRBS2 protein, human; D016601:RNA-Binding Proteins
keywords: Alzheimer; Complex trait analysis; Epistasis; GWAI; Replication