Genome-wide association interaction analysis for Alzheimer's diseaseGenome-wide association interaction analysis for Alzheimer's disease
Van Broeckhoven, Christine
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
VIB DMG - Neurodegenerative Brain Diseases Group
2014Fayetteville, N.Y., 2014
Neurobiology of aging. - Fayetteville, N.Y.
35(2014):11, p. 2436-2443
University of Antwerp
We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic datacombining 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 (beta = -0.19, p = 0.0006) and cerebellum (beta = -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. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved.