[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Gusareva, Elena ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Carrasquillo, Minerva M.; Mayo Clinic Florida > Department of Neuroscience
Bellenguez, Céline; Unité d'Epidémiologie et de Santé Publique > INSERM U744
Cuyvers, Elise; Institute Born-Bunge, University of Antwerp > Department of Molecular Genetics, VIB
Colon, Samuel; Mayo Clinic Florida > Department of Neuroscience
Graff-Radford, Neill R.; Mayo Clinic Florida > Department of Neurology
Petersen, Ronald C.; Mayo Clinic Florida > Department of Neurology
Dickson, Dennis W.; Mayo Clinic Florida > Department of Neuroscience
Mahachie John, Jestinah ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Bessonov, Kyrylo ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Van Broeckhoven, Christine; Institute Born-Bunge, University of Antwerp > Department of Molecular Genetics VIB
Harold, Denise; Cardiff University School of Medicine, Institute of Psychological Medicine and Clinical Neurosciences > Medical Research Council Centre for Neuropsychiatric Genetics and Genomics
Williams, Julie; Cardiff University School of Medicine, Institute of Psychological Medicine and Clinical Neurosciences > Medical Research Council Centre for Neuropsychiatric Genetics and Genomics
Amouyel, Philippe; Unité d'Epidémiologie et de Santé Publique > INSERM U744
Sleegers, Kristel; Institute Born-Bunge, University of Antwerp > Department of Molecular Genetics VIB
Ertekin-Taner, Nilüfer; Mayo Clinic Florida > Department of Neurology
Lambert, Jean-Charles; Unité d'Epidémiologie et de Santé Publique > INSERM U744
Van Steen, Kristel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
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