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Genome-wide association interaction analysis for Alzheimer's disease

Gusareva, Elena S., Carrasquillo, Minerva M., Bellenguez, Céline, Cuyvers, Elise, Colon, Samuel, Graff-Radford, Neill R., Petersen, Ronald C., Dickson, Dennis W., Mahachie John, Jestinah M., Bessonov, Kyrylo, Van Broeckhoven, Christine, Harold, Denise, Williams, Julie, Amouyel, Philippe, Sleegers, Kristel, Ertekin-Taner, Nilüfer, Lambert, Jean-Charles and Van Steen, Kristel 2014. Genome-wide association interaction analysis for Alzheimer's disease. Neurobiology of Aging 35 (11) , pp. 2436-2443. 10.1016/j.neurobiolaging.2014.05.014

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Elsevier
ISSN: 0197-4580
Last Modified: 14 Mar 2019 11:47

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